Farnesyl transferase inhibiting tricyclic quinazoline derivatives substituted with carbon-linked imidazoles or triazoles

ABSTRACT

This invention comprises the novel compounds of formula (I) wherein r, s, t, R 1 , R 2 , R 3 , R 4 , R 5 , and R 6  have defined meanings, having farnesyl transferase inhibiting activity; their preparation, compositions containing them and their use as a medicine.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a National Stage application under 35 U.S.C. § 371of International Application No. PCT/EP03/03986 filed 14 Apr. 2003,which claims priority from EP02076448.6, filed 15 Apr. 2002, thecontents of which are hereby incorporated by reference.

The present invention is concerned with novel tricyclic quinazolinederivatives substituted with carbon-linked imidazoles or triazoles, thepreparation thereof, pharmaceutical compositions comprising said novelcompounds and the use of these compounds as a medicine as well asmethods of treatment by administering said compounds.

Oncogenes frequently encode protein components of signal transductionpathways which lead to stimulation of cell growth and mitogenesis.Oncogene expression in cultured cells leads to cellular transformation,characterized by the ability of cells to grow in soft agar and thegrowth of cells as dense foci lacking the contact inhibition exhibitedby non-transformed cells. Mutation and/or overexpression of certainoncogenes is frequently associated with human cancer. A particular groupof oncogenes is known as ras which have been identified in mammals,birds, insects, mollusks, plants, fungi and yeasts. The family ofmammalian ras oncogenes consists of three major members (“isoforms”):H-ras, K-ras and N-ras oncogenes. These ras oncogenes code for highlyrelated proteins generally known as p21^(ras). Once attached to plasmamembranes, the mutant or oncogenic forms of p21^(ras) will provide asignal for the transformation and uncontrolled growth of malignant tumorcells. To acquire this transforming potential, the precursor of thep21^(ras) oncoprotein must undergo an enzymatically catalyzedfarnesylation of the cysteine residue located in a carboxyl-terminaltetrapeptide. Therefore, inhibitors of the enzymes that catalyzes thismodification, i.e. farnesyl transferase, will prevent the membraneattachment of p21^(ras) and block the aberrant growth of ras-transformedtumors. Hence, it is generally accepted in the art that farnesyltransferase inhibitors can be very useful as anticancer agents fortumors in which ras contributes to transformation.

Since mutated oncogenic forms of ras are frequently found in many humancancers, most notably in more than 50% of colon and pancreaticcarcinomas (Kohl et al., Science, vol 260, 1834-1837, 1993), it has beensuggested that farnesyl tranferase inhibitors can be very useful againstthese types of cancer.

In EP-0,371,564 there are described (1H-azol-1-ylmethyl) substitutedquinoline and quinolinone derivatives which suppress the plasmaelimination of retinoic acids. Some of these compounds also have theability to inhibit the formation of androgens from progestines and/orinhibit the action of the aromatase enzyme complex.

In WO 97/16443, WO 97/21701, WO 98/40383 and WO 98/49157, there aredescribed 2-quinolone derivatives which exhibit farnesyl transferaseinhibiting activity. WO 00/39082 describes a class of novel1,2-annelated quinoline compounds, bearing a nitrogen- or carbon-linkedimidazole, which show farnesyl protein transferase and geranylgeranyltransferase inhibiting activity. Other quinolinone and quinazolnecompounds having farnesyl transferase inhibiting activity are describedin WO 00/12498, WO 00/12499, WO 00/47574, WO 01/53289, WO 01/98302, WO02/24682, WO 02/24683, WO 02/24686 and WO 02/24687.

Unexpectedly, it has been found that the present novel compounds, allhaving a phenyl substituent on the 4-position of the 2,3-annelatedquinolinone moiety bearing a carbon-linked imidazole or triazole, showfarnesyl protein transferase inhibiting activity. The present compoundscan have advantageous properties with regard to solubility andstability.

The present invention concerns compounds of formula (I):

or a pharmaceutically acceptable salt or N-oxide or stereochemicallyisomeric form thereof, wherein

-   r and s are each independently 0, 1, 2 or 3;-   t is 0, 1, or 2;-   each R¹ and R² are independently hydroxy, halo, cyano, nitro,    C₁₋₆alkyl, —(CR¹⁶R¹⁷)_(p) —C₃₋₁₀cycloalkyl, cyanoC₁₋₆alkyl,    hydroxyC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl, hydroxycarbonylC₁₋₆alkyl,    R²⁰SC₁₋₆alkyl, trihalomethyl, arylC₁₋₆alkyl, Het¹C₁₋₆alkyl,    —C₁₋₆alkyl-NR¹⁸R¹⁹, —C₁₋₆alkylNR¹⁸C₁₋₆alkyl-NR¹⁸R¹⁹,    —C₁₋₆alkylNR¹⁸COC₁₋₆alkyl, —C₁₋₆alkylNR¹⁸COAlkAr¹,    —C₁₋₆alkylNR¹⁸COAr¹, C₁₋₆alkylsulphonylaminoC₁₋₆alkyl, C₁₋₆alkyloxy,    hydroxyC₁₋₆alkyloxy, C₁₋₆alkyloxyC₁₋₆alkyloxy, —OC₁₋₆alkyl-NR¹⁸R¹⁹,    trihalomethoxy, arylC₁₋₆alkyloxy, Het¹C₁₋₆alkyloxy, C₂₋₆alkenyl,    cyanoC₂₋₆alkenyl, —C₂₋₆alkenyl-NR¹⁸R¹⁹, hydroxycarbonylC₂₋₆alkenyl,    C₁₋₆alkyloxycarbonylC₂₋₆alkenyl, C₂₋₆alkynyl, —CHO,    C₁₋₆alkylcarbonyl, hydroxyC₁₋₆alkylcarbonyl, hydroxycarbonyl,    C₁₋₆alkyloxycarbonyl, —CONR¹⁸R¹⁹, —CONR¹⁸—C₁₋₆alkyl-NR¹⁸R¹⁹,    —CONR¹⁸—C₁₋₆alkyl-Het¹, —CONR¹⁸—C₁₋₆alkyl-Ar¹, —CONR¹⁸—O—C₁₋₆alkyl,    —CONR¹⁸—C₁₋₆alkenyl, —NR¹⁸R¹⁹, —OC(O)R²⁰, —CR²⁰═NR²¹, —CR²⁰═N—OR²¹,    —NR²⁰C(O)NR¹⁸R¹⁹, —NR²⁰SO₂R²¹, —NR²⁰C(O)R²¹, —S—R²⁰, —S(O)—R²⁰,    —S(O)₂R²⁰, —SO₂NR²⁰R²¹, —C(NR²²R²³)═NR²⁴,    -   or a group of formula        —CO-Z or —CO—NR^(y)—Z        -   in which R^(y) is hydrogen or C₁₋₄alkyl and Z is phenyl or a            5- or 6-membered heterocyclic ring containing one or more            heteroatoms selected from oxygen, sulphur and nitrogen, the            phenyl or heterocyclic ring being optionally substituted by            one or two substituents each independently selected from            halo, cyano, hydroxycarbonyl, aminocarbonyl, C₁₋₆alkylthio,            hydroxy, —NR¹⁸R¹⁹, C₁₋₆alkylsulphonylamino, C₁₋₆alkyl,            haloC₁₋₆alkyl, C₁₋₆alkyloxy or phenyl; or-   two R¹ and R² substituents adjacent to one another on the phenyl    ring may independently form together a bivalent radical of formula    —O—CH₂—O—  (a-1)    —O—CH₂—CH₂—O—  (a-2)    —O—CH═CH—  (a-3)    —O—CH₂—CH₂—  (a-4) or    —O—CH₂—CH₂—CH₂—  (a-5)    -   R¹⁶ and R¹⁷ are independently hydrogen or C₁₋₆ alkyl;    -   R¹⁸ and R¹⁹ are independently hydrogen, C₁₋₆ alkyl or        —(CR¹⁶R¹⁷)_(p) —C₃₋₁₀cycloalkyl, or together with the adjacent        nitrogen atom form a 5- or 6-membered heterocyclic ring        optionally containing one, two or three further heteroatoms        selected from oxygen, nitrogen or sulphur and optionally        substituted by one or two substituents each independently        selected from halo, hydroxy, cyano, nitro, C₁₋₆alkyl,        haloC₁₋₆alkyl, C₁₋₆-alkyloxy, OCF₃, hydroxycarbonyl,        C₁₋₆alkyloxycarbonyl, aminocarbonyl, mono- or        di-(C₁₋₆alkyl)aminocarbonyl, amino, mono- or di(C₁₋₆alkyl)amino,        C₁₋₆alkylsulfonylamino, oxime, or phenyl;    -   R²⁰ and R²¹ are independently hydrogen, C₁₋₆alkyl, —CR¹⁶R¹⁷)_(p)        —C₃₋₁₀cycloalkyl or arylC₁₋₆alkyl;    -   R²², R²³ and R²⁴ are independently hydrogen and C₁₋₆alkyl or        C(O)C₁₋₆alkyl;    -   p is 0 or 1;-   R³ is hydrogen, halo, cyano, C₁₋₆alkyl, —(CR¹⁶R¹⁷)_(p)    —C₃₋₁₀cycloalkyl, haloC₁₋₆alkyl, cyanoC₁₋₆alkyl, hydroxyC₁₋₆alkyl,    C₁₋₆alkyloxyC₁₋₆alkyl, arylC₁₋₆alkyloxy C₁₋₆alkyl,    C₁₋₆alkylthioC₁₋₆alkyl, hydroxycarbonylC₁₋₆alkyl, C₁₋₆alkylcarbonyl    C₁₋₆alkyl, C₁₋₆alkyloxycarbonylC₁₋₆alkyl, —C₁₋₆alkyl-NR¹⁸R¹⁹,    —C₁₋₆alkyl-CONR¹⁸R¹⁹, arylC₁₋₆alkyl, Het¹C₁₋₆alkyl, C₂₋₆alkenyl,    —C₂₋₆alkenyl NR¹⁸R¹⁹, C₂₋₆alkynyl, hydroxycarbonyl,    C₁₋₆alkyloxycarbonyl, aryl, or Het¹; or    -   a radical of formula        —O—R⁷  (b-1)        —S—R⁷  (b-2)        —NR⁸R⁹  (b-3) or        —N═CR⁷R⁸  (b-4)        -   wherein R⁷ is hydrogen, C₁₋₆alkyl, —(CR¹⁶R¹⁷)_(p)            —C₃₋₁₀cycloalkyl, arylC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,            C₁₋₆alkylcarbonyl or —C₁₋₆alkylC(O)OC₁₋₆alkyl NR¹⁸R¹⁹, or a            radical of formula -Alk-OR¹⁰ or -Alk-NR¹¹R¹²;        -   R⁸ is hydrogen, C₁₋₆alkyl, —(CR¹⁶R¹⁷)_(p) —C₃₋₁₀cycloalkyl,            C₂₋₆alkenyl or C₂₋₆alkynyl;        -   R⁹ is hydrogen, hydroxy, C₁₋₆alkyl, —(CR¹⁶R¹⁷)_(p)            —C₃₋₁₀cycloalkyl, C₁₋₆alkylcarbonylC₁₋₆alkyl, arylC₁₋₆alkyl,            C₂₋₆alkenyl, C₂₋₆alkynyl, aryl, C₁₋₆alkyloxy, a group of            formula —NR¹⁸R¹⁹, C₁₋₆alkylcarbonylamino, C₁₋₆alkylcarbonyl,            haloC₁₋₆alkylcarbonyl, arylC₁₋₆alkylcarbonyl, arylcarbonyl,            C₁₋₆alkyloxycarbonyl, trihaloC₁₋₆alkyloxycarbonyl,            C₁₋₆alkyloxyC₁₋₄alkylcarbonyl, aminocarbonyl, mono- or            di(C₁₋₆alkyl)aminocarbonyl wherein the alkyl moiety may            optionally be substituted by one or more substituents            independently selected from aryl and C₁₋₆alkyloxycarbonyl            substituents; aminocarbonylcarbonyl, mono- or            di(C₁₋₆alkyl)aminoC₁₋₆alkylcarbonyl, or a radical of formula            -Alk-OR¹⁰ or Alk-NR¹¹R¹²;            -   wherein Alk is C₁₋₆alkanediyl;        -   R¹⁰ is hydrogen, C₁₋₆alkyl, —(CR¹⁶R¹⁷)_(p) —C₃₋₁₀cycloalkyl,            C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkylcarbonyl or            hydroxyC₁₋₆alkyl;        -   R¹¹ is hydrogen, C₁₋₆alkyl, —(CR¹⁶R¹⁷)_(p) —C₃₋₁₀cycloalkyl,            C₂₋₆alkenyl or C₂₋₆alkynyl;        -   R¹² is hydrogen, C₁₋₆alkyl, —(CR¹⁶R¹⁷)_(p) —C₃₋₁₀cycloalkyl,            C₂₋₆alkenyl, C₂₋₆alkynyl or C₁-alkylcarbonyl;-   R⁴ is a radical of formula

-   -   wherein R¹³ is hydrogen, halo or C₁₋₆alkyl;    -   R¹⁴ is hydrogen or C₁₋₆alkyl;    -   R¹⁵ is hydrogen or C₁₋₆alkyl;

-   R⁵ is cyano, hydroxy, halo, C₁₋₆alkyl, —(CR¹⁶R¹⁷)_(p)    —C₃₋₁₀cycloalkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkyloxy,    hydroxycarbonyl, C₁₋₆alkyloxycarbonyl, or a group of formula    —NR¹⁸R¹⁹ or —CONR¹⁸R¹⁹;

-   R⁶ is hydrogen, C₁₋₆alkyl, —(CR¹⁶R¹⁷)_(p) —C₃₋₁₀cycloalkyl,    cyanoC₁₋₆alkyl, —C₁₋₆alkylCO₂R²⁰, aminocarbonylC₁₋₆alkyl,    —C₁₋₆alkyl-NR¹⁸R¹⁹, R²⁰SO₂, R²⁰SO₂C₁₋₆alkyl, —C₁₋₆alkyl-OR²⁰,    —C₁₋₆alkyl-SR²⁰, —C₁₋₆alkylCONR¹⁸—C₁₋₆alkyl-NR¹⁸R¹⁹,    —C₁₋₆alkylCONR¹⁸—C₁₋₆alkyl-Het¹, —C₁₋₆alkylCONR¹⁸—C₁₋₆alkyl-Ar¹,    —C₁₋₆alkylCONR¹⁸-Het¹, —C₁₋₆-alkylCONR¹⁸Ar¹,    —C₁₋₆alkylCONR¹⁸—O—C₁₋₆alkyl, —C₁₋₆alkylCONR¹⁸—C₁₋₆alkenyl, -Alk-Ar¹    or -AlkHet¹;

-   Ar¹ is phenyl, naphthyl or phenyl or naphthyl substituted by one to    five substituents each independently selected from halo, hydroxy,    cyano, nitro, C₁₋₆alkyl, haloC₁₋₆alkyl, -alkylNR¹⁸R¹⁹, C₁₋₆alkyloxy,    OCF₃, hydroxycarbonyl, C₁₋₆alkyloxycarbonyl, —CONR¹⁸R¹⁹, —NR¹⁸R¹⁹,    C₁₋₆alkylsulfonylamino, oxime, phenyl, or a bivalent substituent of    formula    —O—CH₂—O— or    —O—CH₂—CH₂—O—;

-   Het¹ is a mono- or bi-cyclic heterocyclic ring containing one or    more heteroatoms selected from oxygen, sulphur and nitrogen and    optionally substituted by one or two substituents each independently    selected from halo, hydroxy, cyano, nitro, C₁₋₆alkyl, haloC₁₋₆alkyl,    -alkylNR¹⁸R¹⁹, C₁₋₆alkyloxy, OCF₃, hydroxycarbonyl,    C₁₋₆alkyloxycarbonyl, —CONR¹⁸R¹⁹, —NR¹⁸R¹⁹, C₁₋₆alkylsulfonylamino,    oxime or phenyl.

As used in the foregoing definitions and hereinafter, halo is generic tofluoro, chloro, bromo and iodo; C₁₋₄alkyl defines straight and branchedchain saturated hydrocarbon radicals having from 1 to 4 carbon atomssuch as, e.g. methyl, ethyl, propyl, butyl, 1-methylethyl,2-methylpropyl and the like; C₁₋₆alkyl includes C₁₋₄alkyl and the higherhomologues thereof having 5 to 6 carbon atoms such as, for example,pentyl, 2-methyl-butyl, hexyl, 2-methylpentyl and the like;C₁₋₆alkanediyl defines bivalent straight and branched chained saturatedhydrocarbon radicals having from 1 to 6 carbon atoms, such as, forexample, methylene, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl,1,5-pentanediyl, 1,6-hexanediyl and the branched isomers thereof;haloC₁₋₆alkyl defines C₁₋₆alkyl containing one or more halo substituentsfor example trifluoromethyl; C₂₋₆alkenyl defines straight and branchedchain hydrocarbon radicals containing one double bond and having from 2to 6 carbon atoms such as, for example, ethenyl, 2-propenyl, 3-butenyl,2-pentenyl, 3-pentenyl, 3-methyl-2-butenyl, and the like; C₂₋₆alkynyldefines straight and branched chain hydrocarbon radicals containing onetriple bond and having from 2 to 6 carbon atoms such as, for example,ethynyl, 2-propynyl, 3-butynyl, 2-pentynyl, 3-pentynyl,3-methyl-2-butynyl, and the like; the term “S(O)” refers to a sulfoxideand “S(O)₂” to a sulfone; aryl defines phenyl, naphthalenyl, phenylsubstituted with one or more substituents each independently selectedfrom halo, C₁₋₆alkyl, C₁₋₆alkyloxy, trifluoromethyl, cyano, orhydroxycarbonyl; or naphtalenyl substituted with one or moresubstituents each independently selected from halo, C₁₋₆alkyl,C₁₋₆alkyloxy, trifluoromethyl, cyano or hydroxycarbonyl; C₃₋₁₀cycloalkylincludes cyclic hydrocarbon groups having from 3 to 10 carbons, such ascyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl,cyclohexenyl, cycloheptyl, cyclooctyl and the like.

Pharmaceutically acceptable addition salts encompass pharmaceuticallyacceptable acid addition salts and pharmaceutically acceptable baseaddition salts. The pharmaceutically acceptable acid addition salts asmentioned hereinabove are meant to comprise the therapeutically activenon-toxic acid addition salt forms which the compounds of formula (I)are able to form. The compounds of formula (I) which have basicproperties can be converted in their pharmaceutically acceptable acidaddition salts by treating said base form with an appropriate acid.Appropriate acids comprise, for example, inorganic acids such ashydrohalic acids, e.g. hydrochloric or hydrobromic acid; sulfuric;nitric; phosphoric and the like acids; or organic acids such as, forexample, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic,malonic, succinic (i.e. butanedioic acid), maleic, fumaric, malic,tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic,p-toluenesulfonic, cyclamic, salicylic, p-amino-salicylic, pamoic andthe like acids.

The compounds of formula (I) which have acidic properties may beconverted in their pharmaceutically acceptable base addition salts bytreating said acid form with a suitable organic or inorganic base.Appropriate base salt forms comprise, for example, the ammonium salts,the alkali and earth alkaline metal salts, e.g. the lithium, sodium,potassium, magnesium, calcium salts and the like, salts with organicbases, e.g. the benzathine, N-methyl-D-glucamine, hydrabamine salts, andsalts with amino acids such as, for example, arginine, lysine and thelike.

The term “acid or base addition salts” also comprises the hydrates andthe solvent addition forms which the compounds of formula (I) are ableto form. Examples of such forms are e.g. hydrates, alcoholates and thelike.

The term stereochemically isomeric forms of compounds of formula (I), asused hereinbefore, defines all possible compounds made up of the sameatoms bonded by the same sequence of bonds but having differentthree-dimensional structures which are not interchangeable, which thecompounds of formula (I) may possess. Unless otherwise mentioned orindicated, the chemical designation of a compound encompasses themixture of all possible stereochemically isomeric forms which saidcompound may possess. Said mixture may contain all diastereomers and/orenantiomers of the basic molecular structure of said compound. Allstereochemically isomeric forms of the compounds of formula (I) both inpure form or in admixture with each other are intended to be embracedwithin the scope of the present invention.

Some of the compounds of formula (I) may also exist in their tautomericforms. Such forms although not explicitly indicated in the above formulaare intended to be included within the scope of the present invention.

Whenever used hereinafter, the term “compounds of formula (I)” is meantto include also the pharmaceutically acceptable acid addition salts andall stereoisomeric forms.

A group of interesting compounds consists of those compounds of formula(I) wherein one or more of the following restrictions apply:

-   a) r and s are each independently 0, 1 or 2;-   b) t is 0 or 1;-   c) R¹ is halo, C₁₋₆alkyl, —(CR¹⁶R¹⁷)_(p) —C₃₋₁₀cycloalkyl,    trihalomethyl, cyano, trihalomethoxy, C₂₋₆alkenyl,    hydroxycarbonylC₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkyloxy,    hydroxyC₁₋₆alkyloxy, aminoC₁₋₆alkyloxy, hydroxycarbonyl,    C₁₋₆alkyloxycarbonyl, —CONR¹⁸R¹⁹, or —CH═NOR²¹; or    -   two R¹ substituents adjacent to one another on the phenyl ring        may independently form together a bivalent radical of formula        —O—CH₂—O—  (a-1), or        —O—CH₂—CH₂—O—  (a-2);-   d) R² is halo, cyano, nitro, cyanoC₁₋₆alkyl, hydroxyC₁₋₆alkyl,    —C₁₋₆alkyl NR¹⁸R¹⁹, Het¹C₁₋₆alkyl, cyanoC₂₋₆alkenyl, —NR¹⁸R¹⁹, CHO,    hydroxycarbonyl, C₁₋₆alkyloxycarbonyl, —CO NR¹⁸R¹⁹; or    -   two R² substituents adjacent to one another on the phenyl ring        may independently form together a bivalent radical of formula        —O—CH₂—O—  (a-1), or        —O—CH₂—CH₂—O—  (a-2);-   e) R³ is hydrogen, halo, C₁₋₆alkyl, —(CR¹⁶R¹⁷)_(p) —C₃₋₁₀cycloalkyl,    haloC₁₋₆alkyl, cyanoC₁-alkyl, hydroxyC₁₋₆alkyl,    C₁₋₆alkyloxyC₁₋₆alkyl, —C₁₋₆alkyl NR¹⁸R¹⁹, Het¹C₁₋₆alkyl,    —C₂₋₆alkenyl NR¹⁸R¹⁹, or -Het¹; or a group of formula    —O—R⁷  (b-1), or    —NR⁸R⁹  (b-3),    -   wherein R⁷ is hydrogen, C₁₋₆alkyl, or —(CR¹⁶R¹⁷)_(p)        —C₃₋₁₀cycloalkyl, or a group of formula -Alk-OR¹⁰ or        -Alk-NR¹¹R¹²;    -   R⁸ is hydrogen or C₁₋₆alkyl;    -   R⁹ is hydrogen, hydroxy, C₁₋₆alkyl, —(CR¹⁶R¹⁷)_(p)        —C₃₋₁₀cycloalkyl, C₁₋₆alkyloxy, C₁₋₆alkylcarbonyl,        aminocarbonyl, or a radical of formula -Alk-OR¹⁰ or Alk-NR¹¹R¹²;    -   wherein Alk is C₁₋₆alkanediyl;    -   R¹⁰ is hydrogen, C₁₋₆alkyl or —(CR¹⁶R¹⁷)_(p) —C₃₋₁₀cycloalkyl;    -   R¹¹ is hydrogen, C₁₋₆alkyl, or —(CR¹⁶R¹⁷)_(p) —C₃₋₁₀cycloalkyl;    -   R¹² is hydrogen or C₁₋₆alkyl;-   f) R⁴ is a radical of formula (c-1) or (c-2) wherein    -   R¹³ is hydrogen;    -   R¹⁴ is C₁₋₆alkyl;    -   R¹⁵ is C₁₋₆alkyl;-   g) R⁶ is hydrogen, C₁₋₆alkyl, —C₁₋₆alkylCO₂R²⁰,    —C₁₋₆alkyl-C(O)NR¹⁸R¹⁹, -Alk-Ar¹, -AlkHet¹ or —(CR¹⁶R¹⁷)_(p)    —C₃₋₁₀cycloalkyl,-   h) Het¹ is a 5- or 6-membered monocyclic heterocyclic ring    containing one, two or three heteroatoms selected from oxygen,    sulphur or nitrogen for example pyrrolidinyl, imidazolyl, triazolyl,    pyridyl, pyrimidinyl, furyl, morpholinyl, piperazinyl, piperidinyl,    thiophenyl, thiazolyl or oxazolyl, or a 9- or 10-membered bicyclic    heterocyclic ring especially one in which a benzene ring is fused to    a heterocyclic ring containing one, two or three heteroatoms    selected from oxygen, sulphur or nitrogen for example indolyl,    quinolinyl, benzimidazolyl, benzotriazolyl, benzoxazolyl,    benzothiazolyl or benzodioxolanyl.

Another group of interesting compounds consists of those compounds offormula (I) wherein one or more of the following restrictions apply:

-   a) r is 0, 1 or 2;-   b) s is 0 or 1;-   c) t is 0;-   d) R¹ is halo, cyano, C₁₋₆alkyl or two R¹ substituents ortho to one    another on the phenyl ring may independently form together a    bivalent radical of formula (a-1);-   e) R² is halo, cyano, cyanoC₁₋₆alkyl, hydroxyC₁₋₆alkyl, —C₁₋₆alkyl    NR¹⁸R¹⁹, Het¹C₁₋₆alkyl, CHO, oxime, hydroxycarbonyl, or two R²    substituents ortho to one another on the phenyl ring may    independently form together a bivalent radical of formula (a-1);-   f) R³ is hydrogen, Het¹ or a group of formula (b-1) or (b-3) wherein    -   R⁷ is hydrogen or a group of formula -Alk-OR¹⁰.    -   R⁸ is hydrogen;    -   R⁹ is hydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl, hydroxy,        C₁₋₆alkyloxy or mono- or di(C₁₋₆alkyl)aminoC₁₋₆alkylcarbonyl;    -   Alk is C₁₋₆alkanediyl and R¹⁰ is hydrogen;-   g) R⁴ is a radical of formula (c-1) or (c-2) wherein    -   R¹³ is hydrogen;    -   R¹⁴ is C₁₋₆alkyl;    -   R¹⁵ C₁₋₆alkyl;-   h) R⁶ is C₁₋₆alkyl, —(CR¹⁶R¹⁷)_(p) —C₃₋₁₀cycloalkyl,    —C₁₋₆alkylCO₂R²⁰, aminocarbonylC₁₋₆alkyl, -Alk-Ar¹ or -AlkHet¹;-   i) aryl is phenyl.

A particular group of compounds consists of those interesting compoundsof formula (I) wherein one or more of the following restrictions apply;

-   a) R¹ is 3-chloro or 3-methyl;-   b) R² is 4-chloro, 4-fluoro or 4-cyano;-   c) R⁶ is methyl or —CH₂—C₃₋₁₀cycloalkyl most preferably    —CH₂-cyclopropyl;-   d) R¹⁴ is methyl.

Another particular group of compounds consists of those compounds offormula (I) wherein one or more of the following restrictions apply:

-   a) r is 1, s is 1 and t is 0;-   b) R¹ is halo;-   c) R² is halo, C₁₋₆alkyl, C₁₋₆alkyloxy or C₁₋₆alkyloxycarbonyl;-   d) R³ is hydrogen or a radical of formula (b-1) or (b-3) wherein R⁷    is hydrogen or C₁₋₆alkyl, R⁸ is hydrogen and R⁹ is hydrogen;-   e) R⁴ is a radical of formula (c-1) or (c-2) wherein R¹³ is    hydrogen, R¹⁴ is C₁₋₆lalkyl and R¹⁵ is C₁₋₆alkyl;-   f) R⁶ is hydrogen, C₁₋₆alkyl, —(CH₂)_(p) —C₃₋₁₀cycloalkyl,    —C₁₋₆alkylCO₂C₁₋₆alkyl or -Alk-Ar¹.

A further particular group of compounds consists of those compounds offormula (I) wherein one or more of the following restrictions apply:

-   a) r is 1, s is 1 and t is 0;-   R¹ is halo;-   c) R² is halo, C₁₋₆alkyl or C₁₋₆alkyloxy;-   d) R³ is hydrogen, hydroxy or amino;-   e) R⁴ is a radical of formula (c-1) wherein R¹³ is hydrogen and R¹⁴    is C₁₋₆alkyl;-   f) R⁶ is hydrogen or C₁₋₆alkyl.

An even further particular group of compounds consists of thosecompounds of formula (I) wherein R¹ is halo, C₁₋₆alkyl or forms abivalent radical of formula (a-1); R² is halo, cyano, C₁₋₆alkyl, orC₁₋₆alkyloxy; R³ is hydrogen or a radical of formula (b-1) or (b-3)wherein R⁷ is hydrogen or -Alk-OR¹⁰, R⁸ is hydrogen, R⁹ is hydrogen orC₁₋₆alkylcarbonyl and R¹⁰ is hydrogen; R⁴ is a radical of formula (c-1)or (c-2) wherein R¹³ is hydrogen and R¹⁴ and R¹⁵ are C₁₋₆alkyl; and R⁶is hydrogen, C₁₋₆alkyl, —CH₂—C₃₋₁₀cycloalkyl or —C₁₋₆alkylAr¹.

Preferred compounds are those compounds of formula (I) wherein R¹ ishalo, C₁₋₆alkyl or forms a bivalent radical of formula (a-1); R² ishalo, cyano, C₁₋₆alkyl, or C₁₋₆alkyloxy; R³ is hydrogen or a radical offormula (b-1) or (b-3) wherein R⁷ is hydrogen or -Alk-OR¹⁰, R⁸ ishydrogen, R⁹ is hydrogen or C₁₋₆alkylcarbonyl and R¹⁰ is hydrogen; R⁴ isa radical of formula (c-1) wherein R¹³ is hydrogen and R¹⁴ is C₁₋₆alkyl;and R⁶ is hydrogen, C₁₋₆alkyl, —CH₂—C₃₋₁₀cycloalkyl or —C₁₋₆alkylAr¹.

More preferred compounds are those compounds of formula (I) wherein r is1, s is 1 and t is 0; R¹ is halo; R² is halo, C₁₋₆alkyl, C₁₋₆alkyloxy orC₁₋₆alkyloxycarbonyl; R³ is hydrogen or a radical of formula (b-1) or(b-3) wherein R⁷ is hydrogen or C₁₋₆alkyl, R⁸ is hydrogen and R⁹ ishydrogen; R⁴ is a radical of formula (c-1) or (c-2) wherein R¹³ ishydrogen, R¹⁴ is C₁₋₆alkyl and R¹⁵ is C₁₋₆alkyl; and R⁶ is hydrogen,C₁₋₆alkyl, —(CH₂)_(p) —C₃₋₁₀cycloalkyl, —C₁₋₆alkylCO₂C₁₋₆alkyl or-Alk-Ar¹.

Even more preferred compounds are those compounds of formula (I) whereinr is 1, s is 1 and t is 0; R¹ is halo; R² is halo, C₁₋₆alkyl orC₁₋₆alkyloxy; R³ is hydrogen, hydroxy or amino; R⁴ is a radical offormula (c-1) wherein R¹³ is hydrogen and R¹⁴ is C₁₋₆alkyl; and R⁶ ishydrogen or C₁₋₆alkyl.

Most preferred compounds are compounds No 2, No 5, No 19, No 20 and No23.

The compounds of formula (I) and their pharmaceutically acceptable saltsand N-oxides and stereochemically isomeric forms thereof may beprepared, for example, by the following processes:

a) the compounds of formula (I) wherein R⁴ represents a radical offormula (c-1), R³ is hydroxy and R¹⁴ is C₁₋₆alkyl, said compounds beingreferred to as compounds of formula (I-a-1) may be prepared by reactingan intermediate ketone of formula (II) with an intermediate of formula(III-a-1) wherein R¹⁴ is C₁₋₆alkyl. Said reaction requires the presenceof a suitable strong base, such as, for example, butyl lithium in anappropriate solvent, such as, for example, tetrahydrofuran, and thepresence of an appropriate silane derivative, such as, for example,triethylchlorosilane. During the work-up procedure an intermediatesilane derivative is hydrolyzed. Other procedures with protective groupsanalogous to silane derivatives can also be applied.

b) the compounds of formula (I), wherein R⁴ is a radical of formula(c-1), R³ is hydroxy and R¹⁴ is hydrogen, said compounds being referredto as compounds of formula (I-b-1) may be prepared by reacting anintermediate ketone of formula (II) with an intermediate of formula(III-b-1) wherein P is an optional protective group such as, forexample, a sulfonyl group, e.g. a dimethylamino sulfonyl group, whichcan be removed after the addition reaction. Said reaction requires thepresence of a suitable strong base, such as, for example, butyl lithiumin an appropriate solvent, such as tetrahydrofuran and the presence ofan appropriate silane derivative, such as, for example,triethylchlorosilane. During the work-up procedure an intermediatesilane derivative is hydrolyzed. Other procedures with protective groupsanalogues to silane derivatives can also be applied.

c) compounds of formula (I), wherein R⁴ is a radical of formula (c-2),R¹⁵ is C₁₋₆alkyl and R³ is hydroxy, said compounds being referred to ascompounds of formula (I-a-2), may be prepared by reacting anintermediate ketone of formula (II) with an intermediate triazolereagent of formula (III-a-2) wherein R²⁵ is hydrogen or C₁₋₆alkyl, toform intermediates of formula (IVa-2) and subsequently removing the3-mercapto or the 3-C₁₋₆alkylmercapto group. More in particular, thecompounds of formula (I-a-2) may be prepared by reacting the compound offormula (II) with the triazole reagent (III-a-2), preferably in areaction-inert solvent such as tetrahydrofuran, in the presence of astrong base such as butyl lithium at a temperature ranging from −78° C.to room temperature. Removal of the 3-mercapto group is convenientlyeffected with sodium nitrite, for example in THF/H₂O in the presence ofnitric acid. Removal of, for example, the 3-methylmercapto group isconveniently effected with Raney Nickel in ethanol or acetone.

d) Compounds of formula (I), wherein R⁴ is a radical of formula (c-2),R¹⁵ is hydrogen and R³ is hydroxy, said compounds being referred to ascompounds of formula (I-b-2), may be prepared by reacting anintermediate ketone of formula (II) with an intermediate triazolereagent of formula (III-b-2) wherein P is an optional protective groupsuch as, for example, a sulfonyl group, e.g. a dimethylamino sulfonylgroup, which can be removed after the addition reaction. Said reactionrequires the presence of a suitable strong base, such as, for example,butyl lithium in an appropriate solvent, such as, for example,tetrahydrofuran. During the work-up procedure an intermediate silanederivative is hydrolyzed. Other procedures with protective groupsanalogues to silane derivatives can also be applied.

Compounds of formula (I-a-1), (I-b-1), (I-a-2) and (1-b-2) canoptionally be the subject of one or more of the following conversions inany desired order:

-   (i) converting a compound of formula (I) into a different compound    of formula (I);-   (ii) converting a compound of formula (I) into its corresponding    pharmaceutically acceptable salt or N-oxide thereof;-   (iii) converting a pharmaceutically acceptable salt or N-oxide of a    compound of formula (I) into the parent compound of formula (I);-   (iv) preparing a stereochemical isomeric form of a compound of    formula (I) or a pharmaceutically acceptable salt or N-oxide    thereof.

Examples of the conversion of one compound of formula (I) into adifferent compound of formula (I) include the following reactions:

a) Compounds of formula (I-c) wherein R³ is hydroxy, can be convertedinto compounds of formula (I-d), defined as a compound of formula (I)wherein R³ is hydrogen, by submitting the compounds of formula (I-c) toappropriate reducing conditions, such as, e.g. stirring in acetic acidin the presence of formamide, or treatment with sodiumborohydride/trifluoroacetic acid.

b) Compounds of formula (I-c) can be converted to compounds of formula(I-e) wherein R³ is halo, by reacting the compounds of formula (I-c)with a suitable halogenating agent, such as, e.g. thionyl chloride orphosphorus tribromide. Successively, the compounds of formula (I-e) canbe treated with a reagent of formula H—NR⁸R⁹ in a reaction-inertsolvent, thereby yielding compounds of formula (I-f).

c) Alternatively compounds of formula (I-c) can be converted intocompounds of formula (I-f), for example, by treatment with SOCl₂, andthen NH₃/iPrOH, e.g. in a tetrahydrofuran solvent, or by treatment withacetic acid ammonium salt at a temperature ranging from 120 to 180° C.,or by treatment with sulfamide at a temperature ranging from 120 to 180°C.

d) The compounds of formula (I) may also be converted into each othervia art-known reactions or functional group transformations. A number ofsuch transformations are already described hereinabove. Other examplesare hydrolysis of carboxylic esters to the corresponding carboxylic acidor alcohol; hydrolysis of amides to the corresponding carboxylic acidsor amines; hydrolysis of nitrites to the corresponding amides; aminogroups on imidazole or phenyl may be replaced by a hydrogen by art-knowndiazotation reactions and subsequent replacement of the diazo-group byhydrogen; alcohols may be converted into esters and ethers; primaryamines may be converted into secondary or tertiary amines; double bondsmay be hydrogenated to the corresponding single bond; an iodo radical ona phenyl group may be converted in to an ester group by carbon monoxideinsertion in the presence of a suitable palladium catalyst.

The intermediates and starting materials used in the above-describedprocesses may be prepared in conventional manner using procedures knownin the art for example as described in the above-mentioned patentspecifications WO 97/16443, WO 97/21701, WO 98/40383, WO 98/49157 and WO00/39082.

For example intermediates of formula (V) can be prepared by proceduresdescribed in International Patent Specification No. WO 00/39082, frompage 9 to page 15, or by processes analogues thereto. Intermediates offormula (V) can be further converted in compounds of formula (I) whereinR⁶ is hydrogen said compounds being referred to as compounds of formula(I-g) by heating at 120° C. in an appropriate solvent such as toluene.

In a similar way intermediates of formula (VI) can be converted inintermediates of formula (VII).

The preparation of intermediates of formula (VI) and the furtherconversion of the intermediates of formula (VII) can be preformed asdescribed in International Patent Specification No. WO 98/49157, frompage 11 to page 13, and in International Patent Specification No. WO00/39082, from page 9 to page 15, or by processes analogues thereto.

The compounds of formula (I) and some of the intermediates have at leastone stereogenic center in their structure. This stereogenic center maybe present in a R or a S configuration.

The compounds of formula (I) as prepared in the hereinabove describedprocesses are generally racemic mixtures of enantiomers which can beseparated from one another following art-known resolution procedures.The racemic compounds of formula (I) may be converted into thecorresponding diastereomeric salt forms by reaction with a suitablechiral acid. Said diastereomeric salt forms are subsequently separated,for example, by selective or fractional crystallization and theenantiomers are liberated therefrom by alkali. An alternative manner ofseparating the enantiomeric forms of the compounds of formula (I)involves liquid chromatography using a chiral stationary phase. Saidpure stereochemically isomeric forms may also be derived from thecorresponding pure stereochemically isomeric forms of the appropriatestarting materials, provided that the reaction occursstereospecifically. Preferably if a specific stereoisomer is desired,said compound will be synthesized by stereospecific methods ofpreparation. These methods will advantageously employ enantiomericallypure starting materials.

The compounds of formula (I), the pharmaceutically acceptable acidaddition salts and stereoisomeric forms thereof have valuablepharmacological properties in that they have a potent farnesyl proteintransferase (FPTase) inhibitory effect.

This invention provides a method for inhibiting the abnormal growth ofcells, including transformed cells, by administering an effective amountof a compound of the invention. Abnormal growth of cells refers to cellgrowth independent of normal regulatory mechanisms (e.g. loss of contactinhibition). This includes the abnormal growth of: (1) tumor cells(tumors) expressing an activated ras oncogene; (2) tumor cells in whichthe ras protein is activated as a result of oncogenic mutation ofanother gene; (3) benign and malignant cells of other proliferativediseases in which aberrant ras activation occurs. Furthermore, it hasbeen suggested in literature that ras oncogenes not only contribute tothe growth of tumors in vivo by a direct effect on tumor cell growth butalso indirectly, i.e. by facilitating tumor-induced angiogenesis (Rak.J. et al, Cancer Research, 55, 4575-4580, 1995). Hence,pharmacologically targeting mutant ras oncogenes could conceivablysuppress solid tumor growth in vivo, in part, by inhibitingtumor-induced angiogenesis.

This invention also provides a method for inhibiting tumor growth byadministering an effective amount of a compound of the presentinvention, to a subject, e.g. a mammal (and more particularly a human)in need of such treatment. In particular, this invention provides amethod for inhibiting the growth of tumors expressing an activated rasoncogene by the administration of an effective amount of the compoundsof the present invention. Examples of tumors which may be inhibited, butare not limited to, lung cancer (e.g. adenocarcinoma and includingnon-small cell lung cancer), pancreatic cancers (e.g. pancreaticcarcinoma such as, for example exocrine pancreatic carcinoma), coloncancers (e.g. colorectal carcinomas, such as, for example, colonadenocarcinoma and colon adenoma), prostate cancer including theadvanced disease, hematopoietic tumors of lymphoid lineage (e.g. acutelymphocytic leukemia, B-cell lymphoma, Burkitt's lymphoma), myeloidleukemias (for example, acute myelogenous leukemia (AML)), thyroidfollicular cancer, myelodysplastic syndrome (MDS), tumors of mesenchymalorigin (e.g. fibrosarcomas and rhabdomyosarcomas), melanomas,teratocarcinomas, neuroblastomas, gliomas, benign tumor of the skin(e.g. keratoacanthomas), breast carcinoma (e.g. advanced breast cancer),kidney carcinoma, ovary carcinoma, bladder carcinoma and epidermalcarcinoma.

This invention may also provide a method for inhibiting proliferativediseases, both benign and malignant, wherein ras proteins are aberrantlyactivated as a result of oncogenic mutation in genes. With saidinhibition being accomplished by the administration of an effectiveamount of the compounds described herein, to a subject in need of such atreatment. For example, the benign proliferative disorderneurofibromatosis, or tumors in which ras is activated due to mutationor overexpression of tyrosine kinase oncogenes, may be inhibited by thecompounds of this invention.

The compound according to the invention can be used for othertherapeutic purposes, for example:

-   -   a) the sensitisation of tumors to radiotherapy by administering        the compound according to the invention before, during or after        irradiation of the tumor for treating cancer, for example as        described in WO 00/01411;    -   b) treating athropathies such as rheumatoid arthritis,        osteoarthritis, juvenile arthritis, gout, polyarthritis,        psoriatic arthritis, ankylosing spondylitis and systemic lupus        erythematosus, for example as described in WO 00/01386;    -   c) inhibiting smooth muscle cell proliferation including        vascular proliferative disorders, atherosclerosis and        restenosis, for example as described in WO 98/55124;    -   d) treating inflammatory conditions such as ulcerative colitis,        Crohn's disease, allergic rhinitis, graft vs host disease,        conjunctivitis, asthma, ARDS, Behcets disease, transplant        rejection, uticaria, allergic dermatitis, alopecia greata,        scleroderma, exanthem, eczema, dermatomyositis, acne, diabetes,        systemic lupus erythematosis, Kawasaki's disease, multiple        sclerosis, emphysema, cystic fibrosis and chronic bronchitis;    -   e) treating endometriosis, uterine fibroids, dysfunctional        uterine bleeding and endometrial hyperplasia;    -   f) treating ocular vascularisation including vasculopathy        affecting retinal and choroidal vessels;    -   g) treating pathologies resulting from heterotrimeric G protein        membrane fixation including diseases related to following        biological functions or disorders; smell, taste, light,        perception, neurotransmission, neurodegeneration, endocrine and        exocrine gland functioning, autocrine and paracrine regulation,        blood pressure, embryogenesis, viral infections, immunological        functions, diabetes, obesity;    -   h) inhibiting viral morphogenesis for example by inhibiting the        prenylation or the post-prenylation reactions of a viral protein        such as the large delta antigen of hepatitis D virus; and the        treatment of HIV infections;    -   i) treating polycystic kidney disease;    -   j) suppressing induction of inducible nitric oxide including        nitric oxide or cytokine mediated disorders, septic shock,        inhibiting apoptosis and inhibiting nitric oxide cytotoxicity;    -   k) treating malaria.

The compounds of present invention may be particularly useful for thetreatment of proliferative diseases, both benign and malignant, whereinthe K-ras B isoform is activated as a result of oncogenic mutation.

Hence, the present invention discloses the compounds of formula (I) foruse as a medicine as well as the use of these compounds of formula (I)for the manufacture of a medicament for treating one or more of theabove mentioned conditions.

For the treatment of the above conditions, the compound of the inventionmay be advantageously employed in combination with one or more othermedicinal agents such as anti-cancer agents for example selected fromplatinum coordination compounds for example cisplatin or carboplatin,taxane compounds for example paclitaxel or docetaxel, camptothecincompounds for example irinotecan or topotecan, anti-tumor vincaalkaloids for example vinblastine, vincristine or vinorelbine,anti-tumor nucleoside derivatives for example 5-fluorouracil,gemcitabine or capecitabine, nitrogen mustard or nitrosourea alkylatingagents for example cyclophosphamide, chlorambucil, carrnustine orlomustine, anti-tumor anthracycline derivatives for exampledaunorubicin, doxorubicin or idarubicin; HER2 antibodies for exampletrastzumab; and anti-tumor podophyllotoxin derivatives for exampleetoposide or teniposide; and antiestrogen agents including estrogenreceptor antagonists or selective estrogen receptor modulatorspreferably tamoxifen, or alternatively toremifene, droloxifene, faslodexand raloxifene, or aromatase inhibitors such as exemestane, anastrozole,letrazole and vorozole.

For the treatment of cancer the compounds according to the presentinvention can be administered to a patient as described above, inconjunction with irradiation. Such treatment may be especiallybeneficial, as farnesyl transferase inhibitors can act asradiosensitisers, for example as described in International PatentSpecification WO 00/01411, enhancing the therapeutic effect of suchirradiation.

Irradiation means ionizing radiation and in particular gamma radiation,especially that emitted by linear accelerators or by radionuclides thatare in common use today. The irradiation of the tumor by radionuclidescan be external or internal.

Preferably, the administration of the farnesyl transferase inhibitorcommences up to one month, in particular up to 10 days or a week, beforethe irradiation of the tumor. Additionally, it is advantageous tofractionate the irradiation of the tumor and maintain the administrationof the farnesyl transferase inhibitor in the interval between the firstand the last irradiation session.

The amount of farnesyl protein transferase inhibitor, the dose ofirradiation and the intermittence of the irradiation doses will dependon a series of parameters such as the type of tumor, its location, thepatient's reaction to chemo- or radiotherapy and ultimately is for thephysician and radiologists to determine in each individual case.

The present invention also concerns a method of cancer therapy for ahost harboring a tumor comprising the steps of

-   -   administering a radiation-sensitizing effective amount of a        farnesyl protein transferase inhibitor according to the        invention before, during or after    -   administering radiation to said host in the proximity to the        tumor.

In view of their useful pharmacological properties, the subjectcompounds may be formulated into various pharmaceutical forms foradministration purposes.

To prepare the pharmaceutical compositions of this invention, aneffective amount of a particular compound, in base or acid addition saltform, as the active ingredient is combined in intimate admixture with apharmaceutically acceptable carrier, which carrier may take a widevariety of forms depending on the form of preparation desired foradministration. These pharmaceutical compositions are desirably inunitary dosage form suitable, preferably, for administration orally,rectally, percutaneously, or by parenteral injection. For example, inpreparing the compositions in oral dosage form, any of the usualpharmaceutical media may be employed, such as, for example, water,glycols, oils, alcohols and the like in the case of oral liquidpreparations such as suspensions, syrups, elixirs and solutions; orsolid carriers such as starches, sugars, kaolin, lubricants, binders,disintegrating agents and the like in the case of powders, pills,capsules and tablets.

Because of their ease in administration, tablets and capsules representthe most advantageous oral dosage unit form, in which case solidpharmaceutical carriers are obviously employed. For parenteralcompositions, the carrier will usually comprise sterile water, at leastin large part, though other ingredients, to aid solubility for example,may be included. Injectable solutions, for example, may be prepared inwhich the carrier comprises saline solution, glucose solution or amixture of saline and glucose solution. Injectable suspensions may alsobe prepared in which case appropriate liquid carriers, suspending agentsand the like may be employed. In the compositions suitable forpercutaneous administration, the carrier optionally comprises apenetration enhancing agent and/or a suitable wetting agent, optionallycombined with suitable additives of any nature in minor proportions,which additives do not cause a significant deleterious effect to theskin. Said additives may facilitate the administration to the skinand/or may be helpful for preparing the desired compositions. Thesecompositions may be administered in various ways, e.g., as a transdermalpatch, as a spot-on or as an ointment.

It is especially advantageous to formulate the aforementionedpharmaceutical compositions in dosage unit form for ease ofadministration and uniformity of dosage. Dosage unit form as used in thespecification and claims herein refers to physically discrete unitssuitable as unitary dosages, each unit containing a predeterminedquantity of active ingredient, calculated to produce the desiredtherapeutic effect, in association with the required pharmaceuticalcarrier. Examples of such dosage unit forms are tablets (includingscored or coated tablets), capsules, pills, powder packets, wafers,injectable solutions or suspensions, teaspoonfuls, tablespoonfuls andthe like, and segregated multiples thereof.

Those skilled in the art could easily determine the effective amountfrom the test results presented hereinafter. In general it iscontemplated that a therapeutically effective amount would be from 0.001mg/kg to 100 mg/kg body weight, and in particular from 0.5 mg/kg to 100mg/kg body weight. It may be appropriate to administer the required doseas two, three, four or more sub-doses at appropriate intervalsthroughout the day. Said sub-doses may be formulated as unit dosageforms, for example, containing 0.5 to 500 mg, and in particular 10 mg to500 mg of active ingredient per unit dosage form.

EXPERIMENTAL PART

The following examples are provided for purposes of illustration.

Hereinafter “BTEAC” means benzyltriethylammonium salt, “BuLi” meansn-butyl lithium, “DCM” means dichloromethane, ‘DIPE’ means diisopropylether, “DMA” means N,N-dimethyl-acetamide, “DMF” meansN,N-dimethylformamide, ‘DMSO’ means dimethylsulfoxide, ‘EtOH’ meansethanol, ‘EtOAc’ means ethyl acetate, ‘iPrOH’ means isopropanol, ‘MeOH’means methanol, ‘THF’ means tetrahydrofuran, and ‘mp’ means meltingpoint, ‘kromasil®’ is a spherical, totally silica-based chromatographicpacking material developed by Eka Nobel in Sweden, ‘diastereoisomer (A)’is the first fraction that is eluted after normal chromatography of adiastereoisomeric mixture, ‘diastereoisomer (B)’ is the second fractionthat is eluted after normal chromatography of a diastereoisomericmixture.

A. Preparation of the Intermediates

EXAMPLE A1

a) nBuLi 1.6M in hexane (0.112 mol) was added dropwise at −70° C. underN₂ flow to a mixture of 5-bromo-3-(3-chlorophenyl)-2,1-benzisoxazole(0.097 mol) in THF (300 ml). The mixture was stirred at −70° C. for 15min. A mixture of 4-fluorobenzaldehyde (0.112 mol) in THF (100 ml) wasadded dropwise. The mixture was stirred at −70° C. for 30 min, thenhydrolized and extracted with EtOAc. The organic layer was separated,dried (MgSO₄), filtered and the solvent was evaporated till dryness. Theresidue was taken up in diethyl ether and DIPE. The precipitate wasfiltered off, washed and dried, yielding 9.2 g (26.8%) of3-(3-chlorophenyl)-α-(4-fluorophenyl)-2,1-benzisoxazole-5-methanol(intermediate 1), mp. 171° C.

b) A mixture of intermediate 1 (0.0514 mol) and MnO₂ (18 g) in1,4-dioxane (200 ml) was stirred at 80° C. for 3 hours, then cooled toroom temperature and filtered over celite. The solvent was evaporatedtill dryness. The product was used without further purification,yielding (quant.) of[3-(3-chlorophenyl)-2,1-benzisoxazol-5-yl](4-fluorophenyl)-methanone(intermediate 2), mp. 165° C.

c) A mixture of intermediate 2 (0.0514 mol) in THF (180 ml) was cooledon an ice bath. TiCl₃ 15% in water (180 ml) was added dropwise slowly.The mixture was stirred at room temperature overnight, then poured outinto ice water and extracted with DCM. The organic layer was separated,dried (MgSO₄), filtered and the solvent was evaporated till dryness,yielding 18.2 g (100%) of[2-amino-5-(4-fluorobenzoyl)phenyl](3-chlorophenyl)-methanone(intermediate 3).

d) Trichloro-acetylchloride (0.0848 mol) was added dropwise at 5° C. toa mixture of intermediate 3 (0.0707 mol) in DCM (250 ml) under N₂ flow.The mixture was stirred at 5° C. for 30 minutes. Triethylamine (0.0848mol) was added dropwise at 5° C. The mixture was stirred at 5° C. for 1hour, then at room temperature for 2 hours and poured out into icewater. DCM was added. The mixture was extracted with DCM. The organiclayer was separated, dried (MgSO₄), filtered and the solvent wasevaporated. The residue was crystallized from diethyl ether/DIPE. Theprecipitate was filtered off and dried, yielding 33.7 g (95%) of2,2,2-trichloro-N-[2-(3-chlorobenzoyl)-4-(4-fluorobenzoyl)phenyl]-acetamide(intermediate 4).

e) Acetic acid, ammonium salt (0.135 mol) was added at room temperatureto a mixture of intermediate 4 (0.0675 mol) in DMSO (300 ml). Themixture was stirred at 60° C. for 4 hours, then brought to roomtemperature and poured out into water. The precipitate was filtered,washed with water, taken up in warm CH₃CN, filtered, washed again withCH₃CN, then with diethyl ether and dried under a vacuo, yielding 18.5 g(72%) of intermediate 5. The mother layer was purified by columnchromatography over silica gel (15-40 μm) (eluent: DCM/MeOH:NH₄OH95/5/0.1). The pure fractions were collected and the solvent wasevaporated. The residue was crystallized from 2-propanone/diethyl ether.The precipitate was filtered off and dried, yielding 1.8 g (7%) of4-(3-chlorophenyl)-6-(4-fluorobenzoyl)-2(1H)-quinazolinone (intermediate5), mp. 226° C.

f) Intermediate 5 (0.0528 mol) was added in phosphoryl chloride (200 ml)at room temperature. The mixture was stirred at 100° C. for 3 hours andcooled to room temperature. The solvent was evaporated. The residue wastaken up in DCM. The solvent was evaporated till dryness. The residuewas taken up in DCM, poured out into ice water, neutralised with K₂CO₃solid and extracted with DCM. The organic layer was washed with water,separated, dried (MgSO₄), filtered, and the solvent was evaporated. Theresidue was crystallized from 2-propanone. The precipitate was filteredoff and dried, yielding 8.5 g (40%) of intermediate 6. The mother layerwas evaporated. The residue was purified by column chromatography oversilica gel (eluent: toluene/EtOAc 95/5; 15-35 μm). The pure fractionswere collected and the solvent was evaporated. A part (0.5 g) of theresidue (8.9 g, 42%) was crystallized from 2-propanone. The precipitatewas filtered off and dried, yielding 0.3 g of[2-chloro-4-(3-chlorophenyl)-6-quinazolinyl](4-fluorophenyl)-methanone(intermediate 6), mp. 138° C.

g) BuLi 1.6M in hexane (46.5 ml, 0.0744 mol) was added dropwise at −70°C. to a mixture of 1-methyl-1H-imidazole (0.0744 mol) in THF (70 ml)under N₂ flow. Chlorotriethyl-silane (0.0765 mol) was added dropwise at−70° C. The mixture was stirred at −70° C. for 15 minutes. BuLi 1.6M inhexane (41 ml, 0.0659 mol) was added dropwise at −70° C. The mixture wasstirred at −70° C. for 15 minutes. A solution of intermediate 6 (0.0425mol) in THF (150 ml) was added dropwise at −70° C. The mixture wasstirred at −70° C. for 1 hour and poured out into water. EtOAc wasadded. The mixture was extracted with EtOAc. The organic layer waswashed twice with water, separated, dried (MgSO₄), filtered and thesolvent was evaporated. The residue was purified by columnchromatography over silica gel (15-35 μm) (eluent: DCM/MeOH/NH₄OH97/3/0.5). The pure fractions were collected and the solvent wasevaporated. Part (0.5 g) of the residue (14.6 g, 72%) was crystallizedfrom 2-propanone/CH₃CN. The precipitate was filtered off and dried undera vacuo, yielding 0.17 g of2-chloro-4-(3-chlorophenyl)-α-(4-fluorophenyl)-α-(1-methyl-1H-imidazol-5-yl)-6-quinazolinemethanol(intermediate 7), mp. 212° C.

h) A mixture of intermediate 7 (0.0125 mol) and sodium azide (0.038 mol)in DMF (60 ml) was stirred at 90° C. for 2 hours, then brought to roomtemperature, poured out into ice water and stirred. The precipitate wasfiltered, washed with water, taken up in DCM, filtered, washed withdiethyl ether and dried under a vacuo, yielding 3.5 g (58%) ofintermediate 8. The filtrate was extracted with DCM. The organic layerwas separated, dried (MgSO₄), filtered, and the solvent was evaporated.The residue was purified by column chromatography over silica gel (15-40μm) (eluent: DCM/MeOH/NH₄OH 95/5/0.1). The pure fractions were collectedand the solvent was evaporated. The residue (0.9 g, 15%) wascrystallized from 2-propanone. The precipitate was filtered off anddried, yielding 0.7 g (12%) of5-(3-chlorophenyl)-α-(4-fluorophenyl)-α-(1-methyl-1H-imidazol-5-yl)-tetrazolo[1,5-a]quinazoline-7-methanol(intermediate 8), mp. 200° C.

i) Sodium hydroborate (0.001 mol) was added portionwise at roomtemperature to a mixture of intermediate 8 (0.001 mol) in methanol (5ml). The mixture was stirred at room temperature for 2 hours and pouredout into ice water. DCM was added. The organic layer was washed withwater, separated, dried (MgSO₄), filtered and the solvent wasevaporated. The residue was crystallized from 2-propanone. Theprecipitate was filtered off and dried in a vacuo. The residue (0.35 g,70%) was crystallized from ethanol. The precipitate was filtered off anddried in a vacuo, yielding 0.105 g (21%) of5-(3-chlorophenyl)-α-(4-fluorophenyl)-4,5-dihydro-α-(1-methyl-1H-imidazol-5-yl)-tetrazolo[1,5-a]quinazoline-7-methanol(intermediate 9), mp. 230° C.

EXAMPLE A2

a) 5-bromo-3-(3-chlorophenyl)-2,1-benzisoxazole (0.13 m) was added at−70° C. to THF (300 ml) under N₂ flow. A solution of BuLi (0.143 mol)was added dropwise. The mixture was stirred at −70° C. for 10 minutes. Asolution of N,4-dimethoxy-N-methylbenzamide (0.117 mol) in THF (100 ml)was added dropwise at −70° C. The mixture was stirred at −70° C. for 1hour, poured out on ice/EtOAc and extracted with EtOAc. The organiclayer was separated, dried (MgSO₄), filtered, and the solvent wasevaporated. The residue was crystallized from diethyl ether. Theprecipitate was filtered off and dried under a vacuo, yielding 19.5 g(41%) of[3-(3-chlorophenyl)-2,1-benzisoxazol-5-yl](4-methoxyphenyl)-methanone(intermediate 10).

b) Intermediate 10 (0.0536 mol) was added at room temperature to THF(200 ml). TiCl₃ 15% in water (120 ml) was added dropwise at roomtemperature. The mixture was stirred at room temperature for 3 hours,poured out into ice water and extracted with DCM. The organic layer wasseparated, washed with K₂CO₃ 10% then with water, dried (MgSO₄),filtered and the solvent was evaporated, yielding 20.5 g (quantitative)of [2-amino-5(4-methoxybenzoyl)phenyl](3-chlorophenyl)-methanone(intermediate 11).

c) A mixture of intermediate 11 (0.0536 mol) in DCM (200 ml) was cooledto 5° C. under N₂ flow. A solution of trichloro-acetylchloride (0.0643mol) was added dropwise at 5° C. The mixture was stirred at 5° C. for 30minutes. A solution of triethylamine (0.0643 mol) was added dropwise at5° C. The mixture was stirred at 5° C. for 1 hour then at roomtemperature for 2 hours, poured out into ice water and extracted withDCM. The organic layer was separated, washed with water, dried (MgSO₄),filtered and the solvent was evaporated, yielding 27.4 g (quantitative)of2,2,2-trichloro-N-[2-(3-chlorobenzoyl)-4-(4-methoxybenzoyl)phenyl]-acetamide(intermediate 12).

d) Acetic acid, ammonium salt (0.107 mol) was added at room temperatureto a mixture of intermediate 12 (0.0536 mol) in DMSO (250 ml). Themixture was stirred at 60° C. for 4 hours then brought to roomtemperature, poured out into ice water and stirred. The precipitate wasfiltered, washed with water and taken up in warm CH₃CN. The precipitatewas filtered, washed with diethyl ether and dried under a vacuo,yielding 16.2 g (77%) of intermediate 13. The mother layer wasevaporated. The residue was purified by column chromatography oversilica gel (15-40 μm) (eluent: DCM/MeOH/NH₄OH; 95/5/0.1). The purefractions were collected and the solvent was evaporated. The residue(1.2 g, 6%) was crystallized from 2-propanone. The precipitate wasfiltered off and dried, yielding 0.9 g (4%) of4-(3-chlorophenyl)-6-(4-methoxybenzoyl)-2(1H)quinazolinone (intermediate13), mp. 248° C.

e) Intermediate 13 (0.0432 mol) was added at room temperature tophosphoryl chloride (150 ml). The mixture was stirred at 100° C. for 3hours then brought to room temperature. The solvent was evaporated tilldryness. The residue was taken up in DCM. The solvent was evaporated.The residue was taken up in DCM. The mixture was poured out into icewater, neutralized with K₂CO₃ solid and extracted with DCM. The organiclayer was separated, washed with water, dried (MgSO₄), filtered and thesolvent was evaporated. The residue was crystallized from CH₃CN. Theprecipitate was filtered off and dried under a vacuo, yielding 15.5 g(87%) of intermediate 14. The mother layer was purified by columnchromatography over silica gel (eluent: toluene/EtOAc; 9317; 15-40 μm).The pure fractions were collected and the solvent was evaporated. Theresidue (0.7 g, 4%) was crystallized from 2-propanone. The precipitatewas filtered off and dried under a vacuo, yielding 0.5 g (3%) of[2-chloro-4-(3-chlorophenyl)-6-quinazolinyl](4-methoxyphenyl)-methanone(intermediate 14), mp. 175° C.

f) nBuLi (0.0665 mol) was added dropwise at −70° C. to a solution of1-methyl-1H-imidazole (0.0665 mol) in THF (60 ml) under N₂ flow. Themixture was stirred for 15 minutes. Chlorotriethyl-silane (0.0684 mol)was added dropwise. The mixture was stirred for 15 minutes. nBuli (0.059mol) was added dropwise. The mixture was stirred for 15 minutes. Asolution of intermediate 14 (0.038 mol) in THF (150 ml) was added at−70° C. The mixture was stirred at −70° C. for 1 hour and poured outinto water. EtOAc was added. The mixture was extracted with EtOAc. Theorganic layer was washed with water, separated, dried (MgSO₄), filtered,and the solvent was evaporated. The residue was purified by columnchromatography over silica gel (15-35 μm) (eluent: DCM/MeOH/NH₄OH96/4/0.2). The pure fractions were collected and the solvent wasevaporated, yielding 11 g (59%) of2-chloro-4-(3-chlorophenyl)-α-(4-methoxyphenyl)-α-(1-methyl-1H-imidazol-5-yl)-6-quinazolinemethanol(intermediate 15).

g) A mixture of intermediate 15 (0.0224 mol) and sodium azide (0.067mol) in DMF (120 ml) was stirred at 90° C. for 2 hours, brought to roomtemperature, poured out into ice water and stirred. The precipitate wasfiltered, washed with water and taken up in DCM. The organic layer waswashed with water, separated, dried (MgSO₄), filtered, and the solventwas evaporated. The residue was purified by column chromatography oversilica gel (15-40 μm) (eluent: toluene/iPrOH/NH₄OH 90/10/1). The purefractions were collected and the solvent was evaporated, yielding 9 g(80%) of5-(3-chlorophenyl)-α-(4-methoxyphenyl)-α-(1-methyl-1H-imidazol-5-yl)-tetrazolo[1,5-a]quinazoline-7-methanol(intermediate 16), mp 200° C.

h) NaBH₄ (0.003 mol) was added portionwise at room temperature to amixture of intermediate 16 (0.003 mol) in methanol (15 ml). The mixturewas stirred at room temperature for 2 hours and poured out into icewater. DCM was added. The mixture was extracted with DCM. The organiclayer was separated, dried (MgSO₄), filtered, and the solvent wasevaporated. The residue (1.3 g, 86%) was crystallized from2-propanone/diethyl ether. The precipitate was filtered off and dried,yielding 1 g (67%) of5-(3-chlorophenyl)-4,5-dihydro-α-(4-methoxyphenyl)-α-(1-methyl-1H-imidazol-5-yl)-tetrazolo[1,5-a]quinazoline-7-methanol(intermediate 17), mp. 220° C.

EXAMPLE A3

a) nBuLi 1.6 M in hexane (0.112 mol) was added dropwise at −70° C. underN₂ flow to a mixture of 5-bromo-3-(3-chlorophenyl)-2,1-benzisoxazole(0.097 mol) in THF (300 ml). The mixture was stirred at −70° C. for 15min. A mixture of 4-methylbenzaldehyde (0.112 mol) in THF (100 ml) wasadded dropwise. The mixture was stirred at −70° C. for 30 min, thenhydrolized and extracted with EtOAc. The organic layer was separated,dried (MgSO₄), filtered and the solvent was evaporated till dryness. Theresidue was purified by column chromatography over silica gel (20-45 μm)(eluent: DCM/EtOAc 96/4). The pure fractions were collected and thesolvent was evaporated, yielding 13 g (38.3%) of3-(3-chlorophenyl)-α-(4-methylphenyl)-2,1-benzisoxazole-5-methanol(intermediate 18).

b) A mixture of intermediate 18 (0.071 mol) and MnO₂ (0.287 mol) in1,4-dioxane (250 ml) was stirred at 80° C. for 2 hours, then cooled toroom temperature, filtered over celite and washed with DCM. The solventwas evaporated till dryness, yielding 24.7 g (100%) of[3-(3-chlorophenyl)-2,1-benzisoxazol-5-yl](4-methylphenyl)-methanone(intermediate 19).

c) A mixture of intermediate 19 (0.071 mol) in THF (250 ml) was cooledon an ice bath. TiCl₃ 15% in water (250 ml) was added dropwise. Themixture was stirred at room temperature overnight, then poured out intoice water and extracted with DCM. The organic layer was separated, dried(MgSO₄), filtered and the solvent was evaporated till dryness, yielding20.5 g (82.6%) of[2-amino-5(4-methylbenzoyl)phenyl](3-chlorophenyl)-methanone(intermediate 20).

d) Intermediate 20 (0.0085 mol) was added at 5° C. to DCM (30 ml) underN₂ flow. trichloro-acetyl chloride (0.01 mol) then triethylamine (0.01mol) were added dropwise. The mixture was brought to room temperature,stirred at room temperature for 3 hours, poured out into ice water andextracted with DCM. The organic layer was separated, dried (MgSO₄),filtered, and the solvent was evaporated, yielding 4.2 g (quantitative)of2,2,2-trichloro-N-[2-(3-chlorobenzoyl)-4-(4-methylbenzoyl)phenyl]-acetamide(intermediate 21).

e) A mixture of intermediate 21 (0.0085 mol) and acetic acid, ammoniumsalt (0.0169 mol) in DMSO (42 ml) was stirred at 60° C. for 4 hours thencooled and poured out into ice water. The precipitate was filtered,washed with water, taken up in warm CH₃CN, filtered off and dried undera vacuo, yielding 2.02 g (63%) of4-(3-chlorophenyl)-6-(4-methylbenzoyl)-2(1H)quinazolinone (intermediate22), mp. >260° C.

f) A mixture of intermediate 22 (0.041 mol) in phosphoryl chloride (105ml) was stirred at 100° C. for 4 hours then cooled. The solvent wasevaporated. The residue was taken up DCM. The solvent was evaporated.The residue was taken up in DCM. The mixture was poured out into icewater, basified with K₂CO₃ 10% and extracted. The organic layer wasseparated, washed with water, dried (MgSO₄), filtered and the solventwas evaporated. The residue was crystallized from CH₃CN. The precipitatewas filtered off and dried, yielding 11.4 g (70%) of intermediate 23.The mother layer was evaporated and purified by column chromatographyover silica gel (eluent: cyclohexane/EtOAc; 90/10; 15-40 μm). The purefractions were collected and the solvent was evaporated, yielding 1.7 g(10.5%) of[2-chloro-4-(3-chlorophenyl)-6-quinazolinyl](4-methylphenyl)-methanone(intermediate 23), mp. 156° C.

g) 1-Methyl-1H-imidazole (0.0507 mol) was added at −70° C. to THF (90ml) under N₂ flow. nBuLi (31.5 ml) was added dropwise. The mixture wasstirred at −70° C. for 15 minutes. Chlorotriethyl-silane (0.0522 mol)was added dropwise. The mixture was stirred at −70° C. for 15 minutes.nBuLi (28 ml) was added. The mixture was stirred at −70° C. for 15minutes. A mixture of intermediate 23 (0.029 mol) in THF (115 ml) wasadded dropwise. The mixture was stirred at −70° C. for 1 hour, pouredout into water and extracted with DCM. The organic layer was separated,washed with water, dried (MgSO₄), filtered and the solvent wasevaporated. The residue was purified by column chromatography oversilica gel (15-35 μm) (eluent: DCM/MeOH/NH₄OH; 96/4/0.1). The purefractions were collected and the solvent was evaporated, yielding 9 g(65%). A sample (0.3 g) was crystallized from 2-propanone, Theprecipitate was filtered off and dried, yielding2-chloro-4-(3-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)-α-(4-methylphenyl)-6-quinazolinemethanol(intermediate 24), mp. 220° C.

h) A mixture of intermediate 24 (0.0105 mol) and sodium azide (0.031mol) in DMF (70 ml) was stirred at 90° C. for 2 hours then cooled andpoured out into ice water. The precipitate was filtered and taken up inDCM. The organic layer was washed with water, separated, dried (MgSO₄),filtered, and the solvent was evaporated. The residue was purified bycolumn chromatography over silica gel (15-40 μm) (eluent:DCM/MeOH/NH₄OH; 95/5/0.1). The pure fractions were collected and thesolvent was evaporated, yielding 3.68 g (quantitative) of5-(3-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)-α-(4-methylphenyl)-tetrazolo[1,5-a]quinazoline-7-methanol(intermediate 25), mp. 200° C.

i) A mixture of intermediate 25 (0.0083 mol) in thionyl chloride (80 ml)was stirred at 60° C. for 3 hours, then cooled and the solvent wasevaporated. The residue was taken up in DCM. The solvent was evaporated,yielding7-[chloro(1-methyl-1H-imidazol-5-yl)(4-methylphenyl)methyl]-5-(3-chlorophenyl)-tetrazolo[1,5-a]quinazoline.hydrochloride (1:1) (intermediate 26). This product was used directly inthe next reaction step.

j) A mixture of intermediate 26 (0.0083 mol) in THF (80 ml) was cooledto 5° C. under N₂ flow. NH₃/iPrOH (80 ml) was added dropwise. Themixture was stirred at 5° C. for 1 hours, then brought to roomtemperature. The mixture was stirred at room temperature overnight,poured out into ice water and extracted with DCM. The organic layer wasseparated, washed with water, dried (MgSO₄), filtered and the solventwas evaporated. The residue was purified by column chromatography oversilica gel (15-40 μm) (eluent: DCM/MeOH/NH₄OH 96/4/0.2). The purefractions were collected and the solvent was evaporated. The residue wascrystallized from CH₃CN. The precipitate was filtered off and dried,yielding 1.37 g (33%) of5-(3-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)-α-(4-methylphenyl)-tetrazolo[1,5-a]quinazoline-7-methanaminehydrate (1:1) (intermediate 27), mp. 150° C.

k) Sodium hydroborate (0.0005 mol) was added portionwise at roomtemperature to a mixture of intermediate 27 (0.0005 mol) in methanol(2.5 ml). The mixture was stirred at room temperature for 2 hours andpoured out into ice water. DCM was added. The mixture was extracted withDCM. The organic layer was separated, washed with water, dried (MgSO₄),filtered and the solvent was evaporated. The residue was purified bycolumn chromatography over kromasil® (5 μm) (eluent: DCM/MeOH/Et₃N97/3/0.3). The pure fractions were collected and the solvent wasevaporated. The residue (0.1 g, 40%) was taken up in diethyl ether anddried in a vacuo, yielding 0.07 g (28%) of5-(3-chlorophenyl)-4,5-dihydro-α-(1-methyl-1H-imidazol-5-yl)-α-(4-methylphenyl)-tetrazolo[1,5-a]quinazoline-7-methanamine(intermediate 28), mp. 140° C.

EXAMPLE A4

Preparation of

Sodium tetrahydroborate (0.0011 mol) was added at 5° C. to a mixture of(+)-5-(3-chlorophenyl)-α-(4-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)-tetrazolo[1,5-a]quinazoline-7-methanamine(described in International Application WO01/98302) (0.001 mol) in THF(5 ml) under N₂ flow. The mixture was stirred for 2 hours, poured outinto ice water and extracted with DCM. The organic layer was separated,dried (MgSO₄), filtered, and the solvent was evaporated. The residue waspurified by column chromatography over silica gel (35-70 μm) (eluent:DCM/MeOH/NH₄OH 95/5/0.1). The pure fractions were collected and thesolvent was evaporated. The residue was crystallized from diethyl ether.The precipitate was filtered off and dried, yielding 0.13 g (26%) ofintermediate 29 (S), mp. 180° C.

EXAMPLE A5

a) Preparation of

1-methyl-1H-imidazole (0.0142 mol) was added at −70° C. to THF (14 ml)under N₂ flow. BuLi (0.0142 mol) was added dropwise. The mixture waskept for 15 minutes. Chlorotriethyl-silane (0.0146 mol) was addedslowly. The mixture was kept for 15 minutes. BuLi (0.0126 mol) was addeddropwise. The mixture was kept for 15 minutes. A solution of[2-chloro-4-(3-chlorophenyl)-6-quinazolinyl](4-iodophenyl)-methanone(described in International patent application WO02/24683) (0.0081 mol)in THF (16 ml) was added. The mixture was kept for 1 hour, poured outinto water and extracted with DCM. The organic layer was separated,dried (MgSO₄), filtered, and the solvent was evaporated till dryness.The residue (7.4 g) was purified by column chromatography over silicagel (15-40 μm) (eluent: DCM/MeOH/NH₄OH; 97/3/0.1). The pure fractionswere collected and the solvent was evaporated, yielding 2.3 g (48%) ofintermediate 30.

b) Preparation of

A mixture of intermediate 30 (0.0039 mol) and sodium azide (0.0117 mol)in in DMF (20 ml) was stirred at 140° C. for 1 hour then cooled andpoured out into ice water. The precipitate was filtered, washed withwater several times and taken up in DCM. The organic layer wasseparated, dried (MgSO₄), filtered, and the solvent was evaporated tilldryness. The residue was crystallized from acetonitrile. The precipitatewas filtered off and dried, yielding 1.8 g (78%) of intermediate 31,mp. >260° C.

c) Preparation of

Sodium hydroborate (0.002 mol) was added portionwise at room temperatureto a solution of intermediate 31 (0.002 mol) in MeOH (12 ml). Themixture was stirred at room temperature for 2 hours. Ice and water wereadded. The precipitate was filtered off and dried. EtOAc was added tothe filtrate. The mixture was extracted with DCM. The organic layer wasseparated, dried (MgSO₄), filtered, and the solvent was evaporated,yielding 0.116 g (79%) of intermediate 32.

EXAMPLE A6

a) Preparation of

A mixture of4-(3-chlorophenyl)-6-[2-(4-chlorophenyl)-1,3-dioxolan-2-yl]-2(1H)-quinazolinone(described in International Application WO98/49157) (0.056 mol) inphosphoryl chloride (120 ml) was stirred at 110° C. for 1 hour, thencooled and the solvent was evaporated till dryness. The residue wastaken up in DCM. The organic layer was poured out into diluted NH₄OHcooled with ice and extracted with DCM. The organic layer was separated,dried (MgSO₄), filtered, and the solvent was evaporated. The residue(27.9 g) was purified by column chromatography over silica gel (15-35μm) (eluent: DCM/cyclohexane 80/20). The pure fractions were collectedand the solvent was evaporated. The residue (14 g) was purified bycolumn chromatography over silica gel (15-35 μm) (eluent:cyclohexane/EtOAc 80/20). The pure fractions were collected and thesolvent was evaporated, yielding 11 g (42%) of intermediate 33, mp. 112°C.

b) Preparation of

Sodium azide (0.0108 mol) was added at room temperature to a mixture ofintermediate 33 (0.01 mol) in DMA (50 ml). The mixture was stirred atroom temperature for 48 hours. Water was added. The precipitate wasfiltered, washed with water and dried, yielding 5.9 g (>100%) ofintermediate 34. This product was used directly in the next reactionstep.

c) Preparation of

Sodium hydroborate (0.01 mol) was added portionwise at 5° C. to amixture of intermediate 34 (0.01 mol) in MeOH (75 ml) under N₂ flow. Themixture was stirred at room temperature for 2 hours. Water was added.The precipitate was filtered, washed with DIPE and dried. Part (0.58 g)of the residue (5.8 g) was crystallized from DCM/MeOH. The precipitatewas filtered, washed with diethyl ether and dried, yielding 0.272 g(58%) of intermediate 35, mp. 190° C.

d) Preparation of

A mixture of intermediate 35 (0.009 mol) in toluene (20 ml) and dioxane(25 ml) was stirred at 120° C. for 2 hours. The solvent was evaporatedtill dryness, yielding 4.4 g (105%) of intermediate 36.

e) Preparation of

Sodium hydride 60% in oil (0.0005 mol) was added at room temperature toa mixture of intermediate 36 (0.0005 mol) in THF (3 ml) under N₂ flow.The mixture was stirred at room temperature for 15 minutes. Iodomethane(0.0005 mol) was added. The mixture was stirred for 2 hours. Water wasadded. The mixture was extracted with DCM. The organic layer wasseparated, dried (MgSO₄), filtered, and the solvent was evaporated. Thisfraction (0.15 g) was crystallized from DCM/MeOH/DIPE. The precipitatewas filtered off and dried, yielding 0.137 g (57%) of intermediate 37,mp. 200° C.

f) Preparation of

A mixture of intermediated (0.008 mol) in HCl 3N (35 ml) and MeOH (45ml) was stirred at 60° C. for 5 hours, poured out into ice water andneutralized with NH₄OH. The precipitate was filtered off and dried. Theresidue (3.144 g) was crystallized from DCM/DIPE. The precipitate wasfiltered off and dried, yielding 2.57 g (74%) of intermediate 38, mp.234° C.

EXAMPLE A7

Preparation of

Sodium hydroborate (0.001 mol) was added at room temperature to amixture of intermediate(−)-5-(3-chlorophenyl)-α-(4-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)tetrazolo[1,5-a]quinazoline-7-methanamine(described in International Application WO01/98302) (0.001 mol) in THF(5 ml) under N₂ flow. The mixture was stirred at room temperature for 5hours. Water was added. The mixture was extracted with DCM. The organiclayer was separated, dried (MgSO₄), filtered, and the solvent wasevaporated, yielding 0.5 g of intermediate 39 (R).

B. Preparation of the Final Compounds

EXAMPLE B1

A mixture of(±)-5-(3-chlorophenyl)-α-(4-chlorophenyl)-4,5-dihydro-α-(1-methyl-1H-imidazol-5-yl)tetrazolo[1,5-a]quinazoline-7-methanoldescribed in International application WO00/39082 (0.0013 mol) intoluene (15 ml) was stirred at 120° C. for 6 hours, then cooled to roomtemperature and the solvent was evaporated till dryness. The residue wascrystallized from DCM/MeOH/DIPE. The precipitate was filtered off anddried, yielding 0.19 g (27%) of9-(3-chlorophenyl)-α-(4-chlorophenyl)-4,9-dihydro-α-(1-methyl-1H-imidazol-5-yl)-tetrazolo[5,1-b]quinazoline-7-methanol(compound 1), mp. >260° C.

EXAMPLE B2

A mixture of intermediate 9 (0.0014 mol) in toluene (10 ml) was stirredand refluxed for 48 hours, then brought to room temperature and thesolvent was evaporated till dryness. The residue was taken up in DCM.The solvent was evaporated till dryness. The residue was purified bycolumn chromatography over kromasil® (10 μm) (eluent: DCM/MeOH/Et₃N95/5/0.1). The pure fractions were collected and the solvent wasevaporated. The residue (0.4 g, 57%) was washed with diethyl ether. Theprecipitate was filtered off and dried under a vacuo, yielding 0.35 g(50%) of9-(3-chlorophenyl)-α-(4-fluorophenyl)-4,9-dihydro-α-(1-methyl-1H-imidazol-5-yl)-tetrazolo[5,1-b]quinazoline-7-methanol(compound 2), mp. 180° C.

EXAMPLE B3

A mixture of intermediate 17 (0.0006 mol) in toluene (10 ml) was stirredand refluxed for 5 hours, then brought to room temperature and thesolvent, was evaporated till dryness. The residue was taken up in DCM.The solvent was evaporated till dryness. The residue was purified bycolumn chromatography over kromasil® (10 μm) (eluent: DCM/MeOH/Et₃N95/5/0.5). The pure fractions were collected and the solvent wasevaporated. The residue (0.12 g, 40%) was taken up in DCM. The solventwas evaporated till dryness, yielding 0.08 g (27%) of9-(3-chlorophenyl)-4,9-dihydro-α-(4-methoxyphenyl)-α-(1-methyl-1H-imidazol-5-yl)-tetrazolo[5,1-b]quinazoline-7-methanol(compound 3).

EXAMPLE B4

A mixture of intermediate 28 (0.0001 mol) in toluene (1 ml) was stirredat 120° C. for 6 hours, then brought to room temperature and the solventwas evaporated till dryness. The residue was taken up in DCM. Thesolvent was evaporated till dryness. The residue was purified by columnchromatography over kromasil® (10 μm) (eluent: DCM/MeOH 96/4). Twofractions were collected and the solvent was evaporated, yielding 0.012g (24%) of9-(3-chlorophenyl)-4,9-dihydro-α-(1-methyl-1H-imidazol-5-yl)-α-(4-methylphenyl)-tetrazolo[5,1-b]quinazoline-7-methanamine(diastereoisomer (A)) (compound 4) and 0.01 g (20%) of9-(3-chlorophenyl)-4,9-dihydro-α-(1-methyl-1H-imidazol-5-yl)-α-(4-methylphenyl)-tetrazolo[5,1-b]quinazoline-7-methanamine(diastereoisomer (B)) (compound 5).

EXAMPLE B5

Preparation of

Sodium hydride (0.0005 mol) was added at room temperature to a mixtureof compound 3 (0.0005 mol) in THF (3 ml) under N₂ flow. The mixture wasstirred at room temperature for 30 minutes. Iodomethane (0.0005 mol) wasadded. The mixture was stirred at room temperature for 20 hours. Waterwas added. The mixture was extracted with DCM. The organic layer wasseparated, dried (MgSO₄), filtered, and the solvent was evaporated. Theresidue (0.33 g) was purified by column chromatography over kromasil®(10 μm) (eluent: DCM/MeOH/NH₄OH 92/8/0.2). The pure fractions werecollected and the solvent was evaporated. The residue (0.083 g) wastaken up in diethyl ether. The precipitate was filtered off and dried,yielding 0.06 g (23%) (mixture of diastereoisomers (A/B) (80/20)) ofcompound 6, mp. 149° C.

EXAMPLE B6

Preparation of

A mixture of intermediate 17 (0.0043 mol) in toluene (12.5 ml) anddioxane (12.5 ml) was stirred at 120° C. for 2 hours. The solvent wasevaporated till dryness. The residue was taken up in DCM/MeOH. Thesolvent was evaporated till dryness. The residue (2.05 g, 94%) wascrystallized from DCM/MeOH/CH₃CN. The precipitate was filtered, washedwith diethyl ether and dried, yielding 0.8 g (36%) of compound 7(diastereoisomer (A)), mp. >260° C. The mother layer was evaporated.Part (0.3 g) of the residue (1.3 g) was purified by columnchromatography over silica gel (35-40 μm) (eluent: DCM/iPrOH/NH₄OH90/10/0.1). The pure fractions were collected and the solvent wasevaporated. The residue (0.06 g) was crystallized from DCM/diethylether. The precipitate was filtered off and dried, yielding 0.037 g (7%)of compound 8 (diastereoisomer (B)), mp. 176° C.

EXAMPLE B7

Preparation of

Sodium hydride (0.0012 mol) was added at room temperature to a mixtureof compound 7 (diastereoisomer (A)) (0.0005 mol) in THF (3 ml) under N₂flow. The mixture was stirred at room temperature for 15 minutes.(bromomethyl)-cyclopropane (0.0012 mol) was added. The mixture wasstirred at room temperature for 2 hours, then at 40° C. for 1 hour, thenat 60° C. for 2 hours. DMF (1 ml) was added. The mixture was stirred at60° C. for 1 hour. Water was added. The mixture was extracted withEtOAc. The organic layer was separated, dried (MgSO₄), filtered; and thesolvent was evaporated. The residue (0.38 g) was purified by columnchromatography over kromasil® (10 μm) (eluent: DCM/MeOH 97/3). The purefractions were collected and the solvent was evaporated). This residue(0.075 g, 27%) was crystallized from DIPE. The precipitate was filteredoff and dried, yielding 0.065 g of compound 9, mp. 121° C.

EXAMPLE B8

Preparation of

Thionyl chloride (0.1 ml) was added at room temperature to a mixture ofcompound 1 (0.0002 mol) in EtOH (2 ml). The mixture was stirred at roomtemperature for 2 hours. Water was added. The mixture was taken up inDCM. The organic layer was separated, dried (MgSO₄), filtered, and thesolvent was evaporated. The residue (0.15 g) was purified by columnchromatography over kromasil® (10 μm) (eluent: DCM/MeOH 98/2). The purefractions were collected and the solvent was evaporated. The residue(0.03 g) was taken up in DCM and evaporated till dryness, yielding 0.023g (17%) of compound 10.

EXAMPLE B9

Preparation of

A mixture of intermediate 29 (S) (0.002 mol) in toluene (5 ml) anddioxane (7.5 ml) was stirred at 110° C. for 2 hours, then cooled to roomtemperature. The solvent was evaporated till dryness. The residue (1 g)was purified by column chromatography over silica gel (15-40 μm)(eluent: DCM/MeOH/NH₄OH 93/7/0.1 to 93/7/0.5). Two fractions werecollected and the solvent was evaporated, yielding 0.24 g(diastereoisomer (S) (B)) (24%) F1 and 0.26 g (diastereoisomer (S) (A))(26%) F2. F2 was crystallized from DCM/CH₃CN. The precipitate wasfiltered off and dried, yielding 0.159 g (16%) of compound 12(diastereoisomer (S) (A)), mp. 162° C. F1 was crystallized fromDCM/MeOH/CH₃CN. The precipitate was filtered off and dried, yielding0.157 g (16%) of compound 11 (diastereoisomer (S) (B)), mp. 242° C.

EXAMPLE B10

Preparation of

Sodium hydride (0.0006 mol) was added at room temperature to a mixtureof compound 7 (diastereoisomer (A)) (0.0005 mol) in DMF (3 ml) under N₂flow. The mixture was stirred at room temperature for 30 minutes.Chloro-acetic acid, ethyl ester (0.0006 mol) was added. The mixture wasstirred at room temperature for 1 hour. Water (10 ml) was added. Themixture was stirred at room temperature for 15 minutes. The precipitatewas filtered, washed with DIPE and dried. The residue was dissolved inDCM. The organic layer was dried (MgSO₄), filtered, and the solvent wasevaporated. The residue (0.22 g) was purified by column chromatographyover kromasil® (10 μm) (eluent: DCM/MeOH 97/3). The pure fractions werecollected and the solvent was evaporated. The residue (0.2 g, 68%) wascrystallized from DCM/CH₃CN/DIPE. The precipitate was filtered off anddried, yielding 0.105 g of compound 13 (mixture of diastereoisomers(A/B) (75/25)), mp. 126° C.

EXAMPLE B11

Preparation of

Sodium hydride (0.0006 mol) was added at room temperature to a mixtureof compound 7 (diastereoisomer (A)) (0.0005 mol) in DMF (3 ml) under N₂flow. The mixture was stirred at room temperature for 1 hour. Water wasadded. The precipitate was filtered, washed several times with DIPE anddried. The residue (0.3 g) was purified by column chromatography overkromasil® (10 μm) (eluent: DCM/MeOH 97/3). The pure fractions werecollected and the solvent was evaporated. The residue 0.2 g) wascrystallized from CH₃CN/DIPE. The precipitate was filtered off anddried, yielding 0.12 g of compound 14 (mixture of diastereoisomers (A/B)(65/35)), mp. 164° C.

EXAMPLE B12

Preparation of

Sodium hydride (0.0024 mol) was added portionwise at room temperature toa mixture of compound 3 (0.0021 mol) in DMF (10 ml) under N₂ flow. Themixture was stirred at room temperature for 1 hour. Iodomethane (0.0024mol) was added. The mixture was stirred at room temperature for 2 hoursand 30 minutes. Water (20 ml) was added. The precipitate was filteredand taken up in DCM. The organic layer was separated, dried (MgSO₄),filtered and the solvent was evaporated. The residue (1 g) was purifiedby column chromatography over silica gel (15-40 μm) (eluent:DCM/MeOH/NH4OH 95/5/0.1). The pure fractions were collected and thesolvent was evaporated. The residue (0.74 g 71%) was crystallized fromDCM/CH₃CN/DIPE. The precipitate was filtered off and dried, yielding0.166 g of compound 15 (mixture of diastereoisomers (A/B) (50/50)), mp.144° C.

EXAMPLE B13

Preparation of

A mixture of5-(3-chlorophenyl)-1,5-dihydro-∝-(4-iodophenyl)-∝-(4-methyl-4H-1,2,4-triazol-3-yl)-tetrazolo[1,5-a]quinazoline-7-methanol(described in International Application WO02/24683) (0.0012 mol) intoluene (3.5 ml) and dioxane (5.25 ml) was stirred at 110° C. for 2hours, then cooled to room temperature and the solvent was evaporatedtill dryness. The residue (0.731 g) was crystallized from DCM/MeOH/DIPE.The precipitate was filtered off and dried, yielding 0.367 g of compound16 (mixture of diastereoisomers 77/23), mp. 226° C. The filtrate wasevaporated. The residue (0.34 g) was purified by column chromatographyover silica gel (40 μm) (eluent: toluene/iPrOH/NH₄OH 85/15/1 to80/20/1). The pure fractions were collected and the solvent wasevaporated. The residue (0.07 g) was crystallized from DCM/MeOH/DIPE.The precipitate was filtered off and dried, yielding 0.05 g (7%) ofcompound 17 (diastereoisomer (B)), mp. 195° C.

EXAMPLE B14

Preparation of

A mixture of intermediate 32 (0.0015 mol) in toluene (4.6 ml) anddioxane (6.9 ml) was stirred at 110° C. for 2 hours, then cooled to roomtemperature and the solvent was evaporated till dryness. The residue(1.32 g) was crystallized from DCM/MeOH/DIPE. The precipitate wasfiltered off and dried, yielding 0.85 g (90%) of compound 18, (mixtureof diastereoisomers (A/B) (80/20)), mp. 225° C.

EXAMPLE B15

Preparation of

BuLi 1.6M in hexane (0.0095 mol, 5.95 ml) was added at −78° C. to asolution of 1-methyl-1H-imidazole (0.0095 mol) in THF (8 ml) under N₂flow. The mixture was stirred at −78° C. for 15 minutes.chlorotriethyl-silane (0.0097 mol) was added slowly. The mixture wasstirred at −78° C. for 15 minutes. BuLi 1.6M in hexane (0.0084 mol, 5.27ml) was added. The mixture was stirred at −78° C. for 15 minutes. Asolution of intermediate 38 (0.0054 mol) in THF (9 ml) was addeddropwise. The mixture was stirred at −78° C. for 3 hours, then broughtto 0° C. Water and ice were added. The precipitate was filtered off anddried. DCM was added to the filtrate. The organic layer was separated,dried (MgSO₄), filtered, and the solvent was evaporated. The residue(2.48 g) was purified by column chromatography over silica gel (15-40μm) (eluent: DCM/MeOH/NH₄OH 98/2/0.1 to 94/6/0.5). The pure fractionswere collected and the solvent was evaporated. The residue (0.1 g) wascrystallized from DCM/DIPE. The precipitate was filtered off and dried,yielding 0.031 g (3%) of compound 19 (mixture of diastereoisomers (A/B)(50/50)).

EXAMPLE B16

Preparation of

A mixture of compound 15 (mixture of diastereoisomers (A/B) (50/50))(0.0007 mol) in formamide (2 ml) and acetic acid (4 ml) was stirred at160° C. for 3 hours, poured out into ice/NH₄OH and extracted with DCM.The organic layer was separated, dried (MgSO₄), filtered, and thesolvent was evaporated. The residue (0.55 g) was purified by columnchromatography over silica gel (40 μm) (eluent: DCM/MeOH 97/3). The purefractions were collected and the solvent was evaporated, yielding and0.085 g (23%) of compound 20 (mixture of diastereoisomers (A/B)(60/40)), mp. 108° C.

EXAMPLE B17

Preparation of

Sodium hydride 60% in oil (0.0015 mol) was added portionwise at roomtemperature to a mixture of compound 18 (mixture of diastereoisomers(A/B) (80/20)) (0.0013 mol) in DMF (8 ml) under N₂ flow. The mixture wasstirred at room temperature for 1 hour. Iodomethane (0.0015 mol) wasadded. The mixture was stirred at room temperature for 1 hour. Water wasadded. The precipitate was filtered off and dried. The residue (0.874 g)was purified by column chromatography over silica gel (40 μm) (eluent:DCM/MeOH/NH₄OH 97/3/0.1). The pure fractions were collected and thesolvent was evaporated, yielding: 0.479 g (60%) of compound (R318150) Asample was crystallized from DCM/DIPE. The precipitate was filtered offand dried. Yielding: 0.07 g of compound 21 (mixture of diastereoisomers(A/B) (50/50)), mp. 228° C.

EXAMPLE B18

Preparation of

Sodium hydride 60% in oil (0.0003 mol) was added portionwise at roomtemperature to a mixture of compound 16 (mixture of diastereoisomers(A/B) (77/23)) (0.0002 mol) in DMF (1.5 ml) under N₂ flow. The mixturewas stirred at room temperature for 1 hour. Iodomethane (0.0002 mol) wasadded. The mixture was stirred at room temperature for 1 hour and 30minutes. Water was added. The precipitate was filtered. EtOAc was addedto the filtrate. The organic layer was separated, dried (MgSO₄),filtered, and the solvent was evaporated. The residue (0.08 g) waspurified by column chromatography over silica gel (40 μm) (eluent:DCM/MeOH/NH₄OH 95/5/0.1). The pure fractions were collected and thesolvent was evaporated. The residue (0.071 g) was crystallized fromCH₃CN/DCM. The precipitate was filtered off and dried, yielding 0.054 gof compound 22 (mixture of diastereoisomers (A/B) (87/13)), mp. 81° C.

EXAMPLE B19

Preparation of

A mixture of intermediate 39 (R) (0.001 mol) in toluene (3 ml) anddioxane (3 ml) was stirred at 110° C. for 3 hours, then cooled to roomtemperature and the solvent was evaporated till dryness. The residue(0.6 g) was purified by column chromatography over kromasil® (10 μm)(eluent: DCM/MeOH/NH₄OH 93/7/0.5). The pure fractions were collected andthe solvent was evaporated. This fraction (0.29 g) was crystallized fromDCM/DIPE. The precipitate was filtered off and dried, yielding 0.1 g(20%) of compound 23 (diastereoisomer (R) (B)), mp. >250° C. Thefiltrate was evaporated. The residue (0.18 g) was taken up in diethylether. The precipitate was filtered off and dried, yielding 0.158 g(31%) of compound 24 (mixture of diastereoisomers (R) (A/B) (80/20)),mp. 183° C.

EXAMPLE B20

Preparation of

A mixture of compound 21 (mixture of diastereoisomers (A/B) (50/50))(0.0006 mol), acetic acid palladium(2+) salt (0.00007 mol),triphenyl-phosphine (0.001 mol) and potassium carbonate (0.0013 mol) inDMF (4 ml) and 2-propanol (4 ml) was stirred at 90° C. for 18 hoursunder a 5 bar pressure of CO, then cooled to room temperature andfiltered over celite. Celite was washed with EtOAc, then with water. Theorganic layer was separated, dried (MgSO₄), filtered, and the solventwas evaporated. The residue (0.94 g) was purified by columnchromatography over silica gel (15-40 μm) (eluent: DCM/MeOH/NH₄OH93/7/0.1). The pure fractions were collected and the solvent wasevaporated. The residue (0.17 g, 43%) was crystallized from diethylether. The precipitate was filtered off and dried, yielding 0.089 g(22%) of compound 25 (mixture of diastereoisomers (A/B) (50/50)), mp.165° C.

Table F-1 lists the compounds that were prepared according to one of theabove EXAMPLEs. The following abbreviations were used in the tables:Co.No. stands for Compound Number, Ex. [Bn^(o)] refers to the samemethod as described in the Bn^(o) examples. Some compounds have beencharacterized via melting point (mp.).

C. Pharmacological Example

EXAMPLE C.1 In Vitro Assay for Inhibition of Farnesyl ProteinTransferase

An in vitro assay for inhibition of farnesyl transferase was performedessentially as described in WO 98/40383, pages 33-34. Herein the effectsof test compounds are expressed as pIC₅₀ (the negative log value of theIC₅₀-value) and as % of inhibition at 10⁻⁷ M (see Table F-2)

EXAMPLE C.2 Ras-Transformed Cell Phenotype Reversion Assay

The ras-transformed cell phenotype reversion assay can be performedessentially as described in WO 98/40383, pages 34-36.

TABLE F-2 Table F-2 lists the results of the compounds that were testedaccording to example C.1. Enzyme % of activity inhibition Co. No. pIC50at 10⁻⁷ M 1 7.596 81 2 8.753 96 3 7.632 80 4 7.461 74 5 >9 99 6 7.851 907 >7 64 8 7.906 88 9 7.686 82 10 <7 43 11 <7 46 12 <7 42 13 7.596 80 147.731 74 15 7.78 88 16 <7 45 17 <7 42 18 7.524 76 19 8.013 92 20 8.03691 21 7.718 78 22 >7 57 23 8.595 98 24 7.933 88 25 >7 66D. Composition Example: Film-Coated TabletsPreparation of Tablet Core

A mixture of 100 g of a compound of formula (I), 570 g lactose and 200 gstarch is mixed well and thereafter humidified with a solution of 5 gsodium dodecyl sulfate and 10 g polyvinyl-pyrrolidone in about 200 ml ofwater. The wet powder mixture is sieved, dried and sieved again. Thenthere are added 100 g microcrystalline cellulose and 15 g hydrogenatedvegetable oil. The whole is mixed well and compressed into tablets,giving 10.000 tablets, each comprising 10 mg of a compound of formula(I).

Coating

To a solution of 10 g methyl cellulose in 75 ml of denaturated ethanolthere is added a solution of 5 g of ethyl cellulose in 150 ml ofdichloromethane. Then there are added 75 ml of dichloromethane and 2.5ml 1,2,3-propanetriol 10 g of polyethylene glycol is molten anddissolved in 75 ml of dichloromethane. The latter solution is added tothe former and then there are added 2.5 g of magnesium octadecanoate, 5g of polyvinyl-pyrrolidone and 30 ml of concentrated colour suspensionand the whole is homogenated. The tablet cores are coated with the thusobtained mixture in a coating apparatus.

1. A compound of formula (I):

or a pharmaceutically acceptable salt or N-oxide or stereochemically isomeric form thereof, wherein r and s are each independently 0, 1, 2 or 3; t is 0, 1, or 2; each R¹ and R² are independently hydroxy, halo, cyano, nitro, C₁₋₆alkyl, —(CR¹⁶R¹⁷)_(p) —C₃₋₁₀cycloalkyl, cyanoC₁₋₆alkyl, hydroxyC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl, hydroxycarbonylC₁₋₆alkyl, R²⁰SC₁₋₆alkyl, trihalomethyl, arylC₁₋₆alkyl, Het¹C₁₋₆alkyl, —C₁₋₆alkyl-NR¹⁸R¹⁹, —C₁₋₆alkylNR¹⁸C₁₋₆alkyl-NR¹⁸R¹⁹, —C₁₋₆alkylNR¹⁸COC₁₋₆alkyl, —C₁₋₆alkylNR¹⁸COAlkAr¹, —C₁₋₆alkylNR¹⁸COAr¹, C₁₋₆alkylsulphonylaminoC₁₋₆alkyl, C₁₋₆alkyloxy, hydroxyC₁₋₆alkyloxy, C₁₋₆alkyloxyC₁₋₆alkyloxy, —OC₁₋₆alkyl-NR¹⁸R¹⁹, trihalomethoxy, arylC₁₋₆alkyloxy, Het¹C₁₋₆alkyloxy, C₂₋₆alkenyl, cyanoC₂₋₆alkenyl, —C₂₋₆alkenyl-NR¹⁸R¹⁹, hydroxycarbonylC₂₋₆alkenyl, C₁₋₆alkyloxycarbonylC₂₋₆alkenyl, C₂₋₆alkynyl, —CHO, C₁₋₆alkylcarbonyl, hydroxyC₁₋₆alkylcarbonyl, hydroxycarbonyl, C₁₋₆alkyloxycarbonyl, —CONR¹⁸R¹⁹, —CONR¹⁸—C₁₋₆alkyl-NR¹⁸R¹⁹, —CONR¹⁸—C₁₋₆alkyl-Het¹, —CONR¹⁸—C₁₋₆alkyl-Ar¹, —CONR¹⁸—O—C₁₋₆alkyl, —CONR¹⁸—C₁₋₆alkenyl, —NR¹⁸R¹⁹, —OC(O)R²⁰, —CR²⁰═NR²¹, —CR²⁰═N—OR²¹, —NR²⁰C(O)NR¹⁸R¹⁹, —NR²⁰SO₂R²¹, —NR²⁰C(O)R²¹, —S—R²⁰, —S(O)—R²⁰, —S(O)₂R²⁰, —SO₂NR²⁰R²¹, —C(NR²²R²³)═NR²⁴, or a group of formula —CO-Z or —CO—NR^(y)-Z  in which R^(y) is hydrogen or C₁₋₄alkyl and Z is phenyl or a 5- or 6-membered heterocyclic ring containing one or more heteroatoms selected from oxygen, sulphur and nitrogen, the phenyl or heterocyclic ring being optionally substituted by one or two substituents each independently selected from halo, cyano, hydroxycarbonyl, aminocarbonyl, C₁₋₆alkylthio, hydroxy, —NR¹⁸R¹⁹, C₁₋₆alkylsulphonylamino, C₁₋₆alkyl, haloC₁₋₆alkyl, C₁₋₆alkyloxy or phenyl; or two R¹ and R² substituents adjacent to one another on the phenyl ring may independently form together a bivalent radical of formula —O—CH₂—O—  (a-1) —O—CH₂—CH₂—O—  (a-2) —O—CH═CH—  (a-3) —O—CH₂—CH₂—  (a-4) or —O—CH₂—CH₂—CH₂—  (a-5)  R¹⁶ and R¹⁷ are independently hydrogen or C₁₋₆ alkyl;  R¹⁸ and R¹⁹ are independently hydrogen, C₁₋₆ alkyl or —(CR¹⁶R¹⁷)_(p) —C₃₋₁₀cycloalkyl, or together with the adjacent nitrogen atom form a 5- or 6-membered heterocyclic ring optionally containing one, two or three further heteroatoms selected from oxygen, nitrogen or sulphur and optionally substituted by one or two substituents each independently selected from halo, hydroxy, cyano, nitro, C₁₋₆alkyl, haloC₁₋₆alkyl, C₁₋₆alkyloxy, OCF₃, hydroxycarbonyl, C₁₋₆alkyloxycarbonyl, aminocarbonyl, mono- or di-(C₁₋₆alkyl)aminocarbonyl, amino, mono- or di(C₁₋₆alkyl)amino,  C₁₋₆alkylsulfonylamino, oxime, or phenyl;  R²⁰ and R²¹ are independently hydrogen, C₁₋₆alkyl, —(CR¹⁶R¹⁷)p-C₃₋₁₀cycloalkyl or arylC₁₋₆alkyl;  R²², R²³ and R²⁴ are independently hydrogen and C₁₋₆alkyl or C(O)C₁₋₆alkyl;  p is 0 or 1; R³ is hydrogen, halo, cyano, C₁₋₆alkyl, —(CR¹⁶R¹⁷)_(p) —C₃₋₁₀cycloalkyl, haloC₁₋₆alkyl, cyanoC₁₋₆alkyl, hydroxyC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl, arylC₁₋₆alkyloxy C₁₋₆alkyl, C₁₋₆alkylthioC₁₋₆alkyl, hydroxycarbonylC₁₋₆alkyl, C₁₋₆alkylcarbonyl C₁₋₆alkyl, C₁₋₆alkyloxycarbonylC₁₋₆alkyl, —C₁₋₆alkyl-NR¹⁸R¹⁹, —C₁₋₆alkyl-CONR¹⁸R¹⁹, arylC₁₋₆alkyl, Het¹C₁₋₆alkyl, C₂₋₆alkenyl, —C₂₋₆alkenyl NR¹⁸R¹⁹, C₂₋₆alkynyl, hydroxycarbonyl, C₁₋₆alkyloxycarbonyl, aryl, or Het¹; or a radical of formula —O—R⁷  (b-1) —S—R⁷  (b-2) —NR⁸R⁹  (b-3) or —N═CR⁷R⁸  (b-4)  wherein R⁷ is hydrogen, C₁₋₆alkyl, —(CR¹⁶R¹⁷)_(p) —C₃₋₁₀cycloalkyl, arylC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkylcarbonyl or —C₁₋₆alkylC(O)OC₁₋₆alkyl NR¹⁸R¹⁹, or a radical of formula -Alk-OR¹⁰ or -Alk-NR¹¹R¹²;  R⁸ is hydrogen, C₁₋₆alkyl, —(CR¹⁶R¹⁷)_(p) —C₃₋₁₀cycloalkyl, C₂₋₆alkenyl or C₂₋₆alkynyl;  R⁹ is hydrogen, hydroxy, C₁₋₆alkyl, —(CR¹⁶R¹⁷)_(p) —C₃₋₁₀cycloalkyl, C₁₋₆alkylcarbonylC₁₋₆alkyl, arylC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, aryl, C₁₋₆alkyloxy, a group of formula —NR¹⁸R¹⁹, C₁₋₆alkylcarbonylamino, C₁₋₆alkylcarbonyl, haloC₁₋₆alkylcarbonyl, arylC₁₋₆alkylcarbonyl, arylcarbonyl, C₁₋₆alkyloxycarbonyl, trihaloC₁₋₆alkyloxycarbonyl, C₁₋₆alkyloxyC₁₋₆alkylcarbonyl, aminocarbonyl, mono- or di(C₁₋₆alkyl)aminocarbonyl wherein the alkyl moiety may optionally be substituted by one or more substituents independently selected from aryl and C₁₋₆alkyloxycarbonyl substituents; aminocarbonylcarbonyl, mono- or di(C₁₋₆alkyl)aminoC₁₋₆alkylcarbonyl, or a radical of formula -Alk-OR¹⁰ or Alk-NR¹¹R¹²;  wherein Alk is C₁₋₆alkanediyl;  R¹⁰ is hydrogen, C₁₋₆alkyl, —(CR¹⁶R¹⁷)_(p) —C₃₋₁₀cycloalkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkylcarbonyl or hydroxyC₁₋₆alkyl;  R¹¹ is hydrogen, C₁₋₆alkyl, —(CR¹⁶R¹⁷)_(p) —C₃₋₁₀cycloalkyl, C₂₋₆alkenyl or C₂₋₆alkynyl;  R¹² is hydrogen, C₁₋₆alkyl, —(CR¹⁶R¹⁷)_(p) —C₃₋₁₀cycloalkyl, C₂₋₆alkenyl, C₂₋₆alkynyl or C₁₋₆alkylcarbonyl; R⁴ is a radical of formula

 wherein R¹³ is hydrogen, halo or C₁₋₆alkyl;  R¹⁴ is hydrogen or C₁₋₆alkyl; R⁵ is cyano, hydroxy, halo, C₁₋₆alkyl, —(CR¹⁶R¹⁷)_(p) —C₃₋₁₀cycloalkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkyloxy, hydroxycarbonyl, C₁₋₆alkyloxycarbonyl, or a group of formula —NR¹⁸R¹⁹ or —CONR¹⁸R¹⁹; R⁶ is hydrogen, C₁₋₆alkyl, —(CR¹⁶R¹⁷)_(p) —C₃₋₁₀cycloalkyl, cyanoC₁₋₆alkyl, —C₁₋₆alkylCO₂R²⁰, aminocarbonylC₁₋₆alkyl, —C₁₋₆alkyl-NR¹⁸R¹⁹, R²⁰SO₂, R²⁰SO₂C₁₋₆alkyl, —C₁₋₆alkyl-OR²⁰, —C₁₋₆alkyl-SR²⁰, —C₁₋₆alkylCONR¹⁸—C₁₋₆alkyl-NR¹⁸R¹⁹, —C₁₋₆alkylCONR¹⁸—C₁₋₆alkyl-Het¹, —C₁₋₆alkylCONR¹⁸—C₁₋₆alkyl-Ar¹, —C₁₋₆alkylCONR¹⁸-Het¹, —C₁₋₆alkylCONR¹⁸Ar¹, —C₁₋₆alkylCONR¹⁸—O—C₁₋₆alkyl, —C₁₋₆alkylCONR¹⁸—C₁₋₆alkenyl, -Alk-Ar¹ or -AlkHet¹; Ar¹ is phenyl, naphthyl or phenyl or naphthyl substituted by one to five substituents each independently selected from halo, hydroxy, cyano, nitro, C₁₋₆alkyl, haloC₁₋₆alkyl, -alkylNR¹⁸R¹⁹, C₁₋₆alkyloxy, OCF₃, hydroxycarbonyl, C₁₋₆alkyloxycarbonyl, —CONR¹⁸R¹⁹, —NR¹⁸R¹⁹, C₁₋₆alkylsulfonylamino, oxime, phenyl, or a bivalent substituent of formula —O—CH₂—O— or —O—CH₂—CH₂—O—; Het¹ is a mono- or bi-cyclic heterocyclic ring containing one or more heteroatoms selected from oxygen, sulphur and nitrogen and optionally substituted by one or two substituents each independently selected from halo, hydroxy, cyano, nitro, C₁₋₆alkyl, haloC₁₋₆alkyl, -alkylNR¹⁸R¹⁹, C₁₋₆alkyloxy, OCF₃, hydroxycarbonyl, C₁₋₆alkyloxycarbonyl, —CONR¹⁸R¹⁹, —NR¹⁸R¹⁹, C₁₋₆alkylsulfonylamino, oxime or phenyl.
 2. A compound according to claim 1 wherein r is 1, s is 1 and t is 0; R¹ is halo; R² is halo, C₁₋₆alkyl, C₁₋₆alkyloxy or C₁₋₆alkyloxycarbonyl; R³ is hydrogen or a radical of formula (b-1) or (b-3) wherein R⁷ is hydrogen or C₁₋₆alkyl, R⁸ is hydrogen and R⁹ is hydrogen; R⁴ is a radical of formula (c-1) wherein R¹³ is hydrogen, R¹⁴ is C₁₋₆alkyl; and R⁶ is hydrogen, C₁₋₆alkyl, —(CH₂)_(p) —C₃₋₁₀cycloalkyl, —C₁₋₆alkylCO₂C₁₋₆alkyl or -Alk-Ar¹.
 3. A compound according to claim 1 wherein r is 1, s is 1 and t is 0; R¹ is halo; R² is halo, C₁₋₆alkyl or C₁₋₆alkyloxy; R³ is hydrogen, hydroxy or amino; R⁴ is a radical of formula (c-1) wherein R¹³ is hydrogen and R¹⁴ is C₁₋₆alkyl; and R⁶ is hydrogen or C₁₋₆alkyl.
 4. A compound according to claim 1 selected from the following compounds:


5. A pharmaceutical composition comprising pharmaceutically acceptable carriers and as an active ingredient a therapeutically effective amount of a compound as claimed in claim
 1. 6. A process of preparing a pharmaceutical composition as claimed in claim 5 wherein the pharmaceutically acceptable carriers and the compound are intimately mixed.
 7. A process for the preparation of a compound as claimed in claim 1 which comprises: a) converting intermediates of formula (V) in compounds of formula (I) wherein R⁶ is hydrogen said compounds being referred to as compounds of formula (I-g) by heating at 120° C. in an appropriate solvent; and

b) reacting an intermediate ketone of formula (II) with an intermediate imidazole of formula (Ill-a-1) wherein R¹⁴ is C₁₋₆alkyl with the formation of compounds of formula (I) wherein R⁴ represents a radical of formula (c-1), R³ is hydroxy and R¹⁴ is C₁₋₆alkyl, said compounds being referred to as compounds of formula (I-a-1); and

c) reacting an intermediate ketone of formula (II) with an intermediate imidazole reagent of formula (III-b-1) wherein P is an optional protective group and R¹⁴ is hydrogen and subsequently removal of P with the formation of a compound of formula (I) wherein R⁴ is a radical of formula (c-1), is hydroxy and R¹⁴ is hydrogen said compound being referred to as compounds of formula (I-b-1); and

; and d) optionally effecting one or more of the following conversions in any desired order;  (i) converting a compound of formula (I) into a different compound of formula (I);  (ii) converting a compound of formula (I) into a pharmaceutically acceptable salt or N-oxide thereof;  (iii) converting a pharmaceutically acceptable salt or N-oxide of a compound of formula (I) into the parent compound of formula (I);  (iv) preparing a stereochemical isomeric form of a compound of formula (I) or a pharmaceutically acceptable salt or N-oxide thereof. 